Oxygen in Hormesis Low-Dose Singlet Oxygen

Yael Abraham, Ph.D.

Independent Chief Scientific Consultant

Singlet Oxygen Low-Dose Technology (patented in the U.S., South Korea, China,

India, Mexico, Europe, and other countries worldwide)

Email: [email protected]

Abstract

This review examines the role of singlet oxygen (¹O₂) as a hormetic agent capable of

activating adaptive stress responses without causing oxidative damage. We outline the

molecular mechanisms involved, including Nrf2–Keap1 activation, MAPK signaling, and

autophagy regulation, and discuss evidence from both endogenous processes and novel

non-irradiative gas-phase generation technology. Observational case reports in asthma,

COPD, sleep disorders, anemia, and chemotherapy-related symptoms are presented as

preliminary support for potential therapeutic applications. The review identifies current

knowledge gaps and highlights the need for controlled clinical trials to determine optimal

dosing, safety, and long-term efficacy.

Keywords

Singlet oxygen, oxidative stress, hormesis, Nrf2, autophagy, inflammation,

respiratory disease, immune modulation

1. Introduction

Redox biology has revolutionized our understanding of how organisms manage

internal and environmental challenges. Reactive oxygen species (ROS), once viewed

exclusively as harmful metabolic byproducts, are now recognized as essential signaling

molecules that modulate adaptive stress responses, immune regulation and tissue repair.

Among these ROS, singlet oxygen (¹O₂), an electronically excited form of molecular

oxygen, plays a unique dual role. At high concentrations, it induces oxidative damage and

cytotoxicity; however, at controlled low levels, it may act as a hormetic trigger, initiating

protective pathways that enhance cellular function, immune regulation, and homeostasis.

1

Although singlet oxygen shares functional similarities with other reactive oxygen

species such as superoxide and hydrogen peroxide, it has been comparatively understudiedas a physiological signaling molecule. This is largely due to its extremely short lifespan,

high reactivity, and the difficulty of delivering it in a controlled manner. It is known that

singlet oxygen is generated endogenously in various biological contexts, including

photoactivation in chloroplasts, mitochondrial respiration, and specific enzymatic

reactions.2,3 In these settings, it can modulate key processes such as inflammation,

apoptosis, and redox-sensitive gene regulation. Importantly, low-level exposure to singlet

oxygen has been shown to enhance antioxidant defenses, influence immune cell behavior,

and promote metabolic resilience, all hallmarks of a hormetic response.4

While the hormetic properties of other ROS are well established, the specific

signaling and systemic effects of low-dose singlet oxygen exposure in humans remain

insufficiently studied. Recent advances in non-irradiative generation of singlet oxygen,

particularly through catalytic interactions between air and transition metals, allow for safe,

continuous, and non-invasive delivery of singlet oxygen gas at biologically relevant

concentrations. These developments overcome many of the limitations associated with

traditional photosensitizer-based systems, such as photobleaching, dose inconsistency, and

tissue penetration constraints. As a result, they open new avenues for research into singlet

oxygen’s preventive and regulatory effects in human health, independent of therapeutic

photodynamic contexts.

This review aims to synthesize current understanding of low-dose singlet oxygen

as a hormetic modulator, highlighting its effects on systemic and organ-specific functions,

particularly in immune regulation and stress response pathways. In this first part of the

review, we focus on the mechanistic foundations of singlet oxygen signaling, emerging

clinical observations, and the biological plausibility of its preventive potential. By

integrating experimental insights with real-world exposure data, we propose a framework

for singlet oxygen as a non-pharmacological, redox-based intervention that complements

the body’s innate regulatory networks, inviting further empirical validation and

exploration.

2. Singlet Oxygen: Properties and Generation

2.1. Chemistry and Electronic States of Oxygen

Oxygen constitutes approximately 20% of atmospheric air and is vital for aerobic

life. In its most stable form, dioxygen (O₂) exists as a diradical in the ground triplet state

(³Σg⁻), characterized by two unpaired electrons in separate degenerate orbitals (Figure 1-

a). This electronic configuration imposes spin restrictions on reactions with singlet-state

molecules (which most biological molecules are) but allows reactivity with radicals.Excitation of molecular oxygen leads to two singlet states: ¹Δg and ¹Σg⁺ (Figure 1b

and 1c, respectively). The higher-energy ¹Σg⁺ state is extremely reactive but short-lived,

rapidly relaxing to the lower-energy ¹Δg state, commonly referred to as singlet oxygen

(¹O₂). In the gas phase, isolated singlet oxygen (¹Δg) has a relatively long lifetime (~72

minutes),

5 but this decreases significantly with increased probability of collisions in liquids

or under higher pressure/temperature. Under these conditions, the lifetime can reduce to

mere seconds in the gas phase.6 In solutions, the lifetime of singlet oxygen is even shorter,

ranging from microseconds to nanoseconds, depending on the solvent properties.7

Figure 1 Occupation of molecular orbitals in oxygen at different energetic states: (a) triplet ground state, 3 g

–, (b) Most

stable singlet state, 1 g, (c) Highest energy, short- lived singlet state, 1Σg

+

.

2.2. Singlet Oxygen Generation in Liquid & Gas Phase

Singlet oxygen can be artificially produced through a range of methods, with most

traditional techniques relying on liquid-phase systems. One of the most established ischemical generation,

8 which involves reactions such as the decomposition of trioxidane in

water or reaction of hydrogen peroxide with sodium hypochlorite (Figure 2). This method

is effective in liquids but produces reactive byproducts and has short diffusion range.

Figure 2 Examples for chemical reactions to produce singlet oxygen, 1O2: (a) decomposition of trioxidane in water; (b)

reaction of hydrogen peroxide with sodium hypochlorite.

Another common method is photosensitization,

9 in which light-excitable

compounds (photosensitizers) such as porphyrins transfer energy to ground-state triplet

oxygen, producing singlet oxygen via a type II energy transfer mechanism (Figure 3). This

light-driven process is the foundation of photodynamic therapy (PDT), a clinically

validated modality used in the treatment of certain cancers,10 microbial infections,11 and

dermatological disorders.12 Despite its efficacy, photosensitized singlet oxygen production

requires localized light exposure, often limiting treatment to surface tissues or necessitating

invasive delivery systems. Moreover, outcomes are influenced by complex

pharmacokinetics, oxygen availability, and potential phototoxicity.13 Other methods

include Plasma-induced excitation which generates mixed ROS, including singlet oxygen,

without photosensitizers and laser/microwave excitation which is used primarily in

specialized high-energy applications.Figure 3 Energy diagram illustrating singlet oxygen (1O2) that is generated from ground state triplet oxygen (3O2) via

energy transfer from the excited state of a photosensitizer to the oxygen molecule upon irradiation.

To expand singlet oxygen applications beyond solution-phase systems, alternative

gas-phase generation strategies have been developed.

2.2.1. Singlet Oxygen Generation in Gas Phase

Gas-phase singlet oxygen has a longer intrinsic lifetime and greater diffusion

capacity compared with singlet oxygen generated in liquid or solution-constrained

environments.6 These properties enable non-invasive delivery across larger biological or

environmental surfaces and remove the need for liquid media, photonic targeting, or

pharmacokinetic considerations.

The most common method is photosensitization, in which immobilized dyes (e.g.,

porphyrins, Rose Bengal) absorb light and transfer energy to ground-state oxygen.14

Plasma-based methods employ non-thermal plasma to directly excite molecular oxygen,

generating a mixture of reactive oxygen species (ROS) that includes singlet oxygen,

without the need for light or sensitizers.15 Laser or microwave excitation is primarily used

in high-energy or defense-related contexts.16 More recently, heterogeneous photocatalysis

has been applied, where solid catalysts (e.g., doped TiO₂, ZnO) generate singlet oxygen

from atmospheric oxygen under UV or visible light. 17

A novel non-irradiative catalytic approach produces gas-phase singlet oxygen by

passing ambient air through metal-based substrates engineered to have controlled oxygenaffinity.18 Here, oxygen molecules are transiently adsorbed and excited to the singlet state

before release, without fully oxidizing the metal surface.

19 The yield depends on the metal

alloy composition and airflow parameters, enabling controlled low-dose output suitable for

continuous operation.

In contrast, irradiative photosensitized systems integrate light sources to activate

immobilized sensitizers, producing singlet oxygen via triplet–singlet energy transfer.

While effective in controlled environments, these systems can face challenges in long-term

or low-dose use, including photobleaching, sensitizer degradation, sensitivity to humidity

and temperature, and the need for precise optical alignment. 20 Such factors may limit their

scalability for continuous, unattended clinical or domestic operation.

Although photosensitizer-based gas-phase systems are well established for

laboratory disinfection and air treatment, non-irradiative catalytic platforms offer a light-

independent alternative with fewer maintenance requirements. Their application in

therapeutic contexts remains relatively new, and their physiological implications are

explored in subsequent sections of this review.

2.3. Natural Generation in Plants and Animals

Singlet oxygen is a natural product of various biological processes. For instance,

chlorophyll, that is the green pigment essential for photosynthesis in leaves, can function

as a natural photosensitizer, especially under high light intensity.

21 At these conditions,

singlet oxygen is formed, which, in turn, acts as a signaling molecule, triggering

photoinhibition, which is a protective mechanism that prevents damage to the

photosynthetic apparatus from excessive light exposure.22

In mammalian cells, singlet oxygen is continuously generated through multiple

light-independent pathways. In non-photosensitized tissues, enzymatic systems such as

myeloperoxidase (MPO) in neutrophils and eosinophils generate singlet oxygen during

immune responses. This occurs through MPO-catalyzed reactions involving hydrogen

peroxide and chloride ions, yielding hypochlorous acid (HOCl), which can decompose into

singlet oxygen.

23

Beyond immune cells, singlet oxygen is formed in multiple intracellular

compartments, such as peroxisomes, endoplasmic reticulum, and, most prominently,

mitochondria.24 Mitochondria, the organelles responsible for energy (ATP) production

through aerobic respiration, use oxygen as an electron source. Mitochondrial respiration

inherently produces ROS as byproducts, including hydrogen peroxide (H₂O₂), hydroxyl

radicals (OH•), superoxide anion radicals (O₂•⁻) and singlet oxygen.253. Oxidative Stress, Homeostasis, and Hormesis

3.1. Dose-Dependent Effects and Thresholds of Toxicity

The biological activity of singlet oxygen is defined by a delicate balance between

concentration and exposure duration. The constant production of singlet oxygen in the body

leads to a baseline concentration estimated to be around 10⁻¹³ M under neutral conditions,

which is far below the threshold for cellular damage. In contrast, concentrations reaching

approximately 10⁻⁸ M can damage cell membranes, while local concentrations of 10⁻⁵–10⁻⁴

M are associated with irreversible oxidative damage and cell death.26

Cellular and tissue damage occurs when ROS, including singlet oxygen, oxidize

electron-rich sites, such as double bonds and thiol groups, in key biomolecules (Table 1).

Critical cellular targets include pigments and antioxidants (e.g., chlorophyll, hemoglobin),

proteins (e.g., enzymes, structural and transport proteins, receptors),27 lipids (e.g.,

membrane phospholipids), and nucleic acids.

28 Damage to these macromolecules disrupts

cellular integrity and function, contributing to pathological conditions.

29

Table 1 Chemical activity of singlet oxygen with various biomolecules.

22,26-28

Biomolecule

Type

Key

Reactive

Groups

Reaction Type Example Products Biological

Outcomes

Lipids

(PUFAs)

Allylic

C=C

double

bonds

Ene reaction Lipid hydroperoxides (e.g., 13-

HPODE)

Membrane

damage, lipid

peroxidation

chain reactions,

formation of

signaling

aldehydes (e.g.,

4-HNE),

inflammation

Proteins Trp, His,

Met, Cys

Oxidation of side

chains

Methionine sulfoxide, N-

formylkynurenine, 2-oxo-

histidine

Loss of enzyme

activity, altered

protein folding,

proteasomal

degradation,

redox signaling

Nucleic

Acids

Guanine

(mainly) Base oxidation 8-oxo-7,8-dihydroguanine (8-

oxoG)

Mutagenesis,

transcriptional

errors, impaired

DNA

replication,

contributes to

				age-related diseases and cancer
Cholesterol	Allylic hydrogens, Δ5 double bond	Addition/Oxidation	7-hydroperoxycholesterol, 25- hydroxycholesterol	Altered membrane structure, LXR pathway modulation, potential atherogenesis, implicated in inflammatory diseases
Pigments and antioxidant (e.g., carotenoids, tocopherols)	Conjugated π-systems	Physical/chemical quenching	Inert or less-reactive byproducts	Impair function and protection from oxidative stress

The concept of oxidative stress arises when reactive oxidative species like singlet

oxygen accumulate beyond the buffering capacity of cellular antioxidant systems. The

potential for cellular and tissue damage underscores the importance of preventing ROS

from reaching harmful levels. It has been found that at low concentrations, ROS essentially

act as signalling molecules, as they activate cellular stress-response pathways that include

the upregulation of antioxidant defences and mechanisms to repair existing damage.

1 In

this way, ROS play a crucial role in supporting cellular health and adaptability. By acting

as signalling molecules, they not only alert the system to potential threats but also help

initiate processes that restore balance and promote resilience in the face of environmental

and physiological challenges. For Instance, moderate levels of singlet oxygen have been

shown to enhance mitochondrial activity and stimulate energy metabolism and boost ATP

production.

30 Instead of causing damage, this mild oxidative exposure serves as a signal

that ramps up the cell’s bioenergetic capacity and can activate protective pathways,

effectively priming the cell’s redox defenses.

3.2. The Plasma Membrane as a Redox-Sensitive Platform for Singlet Oxygen

Signaling

At sub-toxic concentrations, singlet oxygen is increasingly recognized not merely

as a byproduct of oxidative metabolism but as a finely tuned signaling mediator that

operates at the cellular interface. These effects have been identified across diverse

biological systems, including plants31,32, bacteria33 and mammals1

. One of its primary sitesof action is the plasma membrane where it chemically modifies specific lipids and proteins,

effectively acting indirectly like receptors that, in turn, trigger or inhibit processes within

the cell.

30,34 Among the most reactive are polyunsaturated fatty acids (PUFAs) in

phospholipids, whose oxidation produces secondary messengers like 4-hydroxynonenal (4-

HNE), known to activate redox-sensitive transcription factors such as Nrf2 and NF-κB.

35

Furthermore, cholesterol, a major component of lipid rafts, is readily oxidized by singlet

oxygen to form cholesterol hydroperoxides and oxysterols, such as 7-ketocholesterol and

25-hydroxycholesterol. These modulate lipid raft dynamics and membrane signaling.

36

These oxidized derivatives influence membrane fluidity and can engage Liver X Receptors

(LXRs) and Toll-like receptors (TLRs), amplifying inflammatory or metabolic responses.

Additionally, singlet oxygen can oxidize cysteine and methionine residues on membrane

proteins, modulating ion channels and receptor conformations.

37 Together, these

modifications convert the plasma membrane into a dynamic redox-sensitive signaling

platform, with singlet oxygen acting as an initiator of downstream adaptive or

immunological responses, leading to a form of stress-response hormesis

3.3. Stress-Response Hormesis: Definition, Mechanisms, and Relevance to

Singlet Oxygen

Hormesis is broadly defined as a biphasic dose-response phenomenon where low levels

of an otherwise harmful agent trigger beneficial adaptive responses, while high levels cause

damage. Within this framework, stress-response hormesis refers specifically to the cellular

and systemic activation of protective pathways in response to low-level stressors that

mildly perturb homeostasis. Such responses are typically transient, self-limiting, and

aimed at enhancing cellular resilience, repair capacity, and metabolic adaptability.38

The hormetic process is evolutionarily conserved across species and encompasses

various stressors including xenobiotic exposure,

39 heat shock,40 caloric restriction and

exercise,

41 hypoxia,42 and mild oxidative stress. These stressors induce cytoprotective

mechanisms such as upregulation of antioxidant enzymes (e.g., superoxide dismutase,

catalase), enhanced DNA repair, autophagy, mitochondrial biogenesis, and immune

modulation.151,43 For example, transient increases in ROS generated during physical

exercise or ischemic preconditioning are known to improve cardiovascular and

neurological outcomes through activation of redox-sensitive pathways like Nrf2, HIF-1α,

and AMPK .44

What distinguishes singlet oxygen as a stress-response hormetic agent is its non-

accumulative, non-reactive decay mechanism. Singlet oxygen naturally and spontaneously

relaxes back to its ground state triplet oxygen, often releasing energy in the form of

phosphorescence or heat, without necessarily undergoing a chemical reaction. This sets it

apart from other ROS such as superoxide or hydrogen peroxide, which must beenzymatically detoxified or can diffuse and cause unintended chain reactions.45 This

inherent reversibility reduces the risk of cumulative oxidative damage during therapeutic

applications, particularly in ambient gas-phase exposures, where its effects are limited in

both time and space.

Additionally, as singlet oxygen’s reactivity can give rise to oxidized lipid-derived

mediators that activate redox‑sensitive pathways such, this bypasses the need for singlet

oxygen itself to accumulate intracellularly.

In summary, singlet oxygen acts as a prototypical agent of stress-response hormesis: it

is transient, does not accumulate, preferentially activates adaptive signaling pathways, and

avoids direct chemical interaction unless at elevated concentrations. These characteristics

make it a promising modality for non-pharmacological preconditioning, immune

modulation, and metabolic resilience. The mechanisms through which singlet oxygen

exerts its hermetic effect will be elaborated upon in the following sections.

4. Hormetic Mechanisms Induced by Singlet Oxygen

Singlet oxygen exerts concentration-dependent effects on biological systems. At

elevated levels, it contributes to oxidative damage and cell death. However, at sub-toxic

concentrations, singlet oxygen triggers a hormetic response, activating intrinsic cellular

defense mechanisms by upregulation of antioxidant enzymes, redox-sensitive signaling,

immune modulation, and autophagic processes. This hormetic response promotes

resilience, repair, and redox homeostasis.

This chapter outlines the molecular pathways and systems influenced by low-dose

singlet oxygen, providing a mechanistic foundation for its therapeutic potential.

4.1. Nrf2-Keap1 Pathway and ARE Gene Activation

One of the primary oxidative stress factors activated by singlet oxygen is Nrf2

(Nuclear factor erythroid 2–related factor 2),46 which plays a critical role in regulating the

antioxidant defense system through the Nrf2-Keap1 pathway. Nrf2 is a transcription factor

that regulates the expression of various antioxidant and cytoprotective genes. Under normal

conditions, Nrf2 is bound to its inhibitor, Keap1 (Kelch-like ECH-associated protein 1),

which promotes its degradation. However, when cells are exposed to singlet oxygen or

other ROS, cysteine residues in Keap1 become oxidized. This oxidation disrupts the

interaction between Nrf2 and Keap1, freeing Nrf2 to move into the nucleus. Inside the

nucleus, Nrf2 binds to antioxidant response elements (ARE) in the promoter regions of

specific genes, stimulating the production of Phase II detoxification and antioxidant

defense enzymes and other various enzymes and proteins involved in cellular protection,

metabolism, redox balance, and stress responses.Major downstream Nrf2 targets include:

4.1.1. Glutathione synthesis

Nrf2 upregulates the catalytic (GCLC) and modifier (GCLM) subunits of

glutamate-cysteine ligase, which is the rate-limiting enzyme in glutathione (GSH)

biosynthesis.47,48 GSH is a tripeptide that acts as a redox buffer that neutralizes hydrogen

peroxide, lipid peroxides,49 and electrophilic agents via enzymatic and non-enzymatic

reactions.50 In addition, it maintains cellular proteins in their reduced thiol form, preventing

aberrant disulfide cross-linking that can impair enzymatic activity and cellular signaling.51

By preserving this thiol-disulfide balance, GSH supports proper protein folding, redox-

sensitive signal regulation, and cytoskeletal organization.52

Importantly, Nrf2-dependent enhancement of GSH synthesis also contributes to

tissue repair mechanisms. Elevated GSH levels facilitate fibroblast migration, reduce

oxidative delay in re-epithelialization, and accelerate wound closure under inflammatory

conditions.53 Thus, GSH not only buffers oxidative stress but orchestrates a redox

environment conducive to tissue regeneration.

While GSH constitutes a primary redox buffer, Nrf2 orchestrates a broader

detoxification and redox-regulatory network, as outlined below.

4.1.2. Detoxification

In addition to enhancing glutathione synthesis, Nrf2 drives the expression of a wide

array of Phase II detoxification enzymes that help neutralize reactive intermediates and

limit their downstream damage. Unlike redox buffers such as GSH that directly scavenge

reactive oxygen species, these enzymes act primarily by converting electrophilic and pro-

oxidant species into more stable and excretable forms, thereby preventing ROS

amplification and preserving cellular integrity.

• NAD(P)H quinone oxidoreductase 1 (NQO1) catalyzes the two-electron

reduction of quinones to hydroquinones, thereby preventing redox cycling and

ROS amplification. 54

• heme oxygenase-1 (HO-1) degrades pro-oxidant heme into biliverdin, free iron,

and carbon monoxide; biliverdin and its product bilirubin act as potent

endogenous antioxidants, while carbon monoxide exhibits anti-inflammatory

effects. 55

• Peroxiredoxins (Prxs) catalyze the reduction of peroxides and modulate redox

signaling by buffering fluctuations in H₂O₂ levels. 56

Together, these detoxification enzymes form a complementary defense layer that

acts upstream of or in concert with antioxidant systems like glutathione. They expand thecell’s capacity to disarm a broad spectrum of harmful metabolites arising from xenobiotic

metabolism, lipid peroxidation, or chronic inflammation. By converting reactive substrates

rather than simply neutralizing ROS, this arm of the Nrf2 response plays a vital role in

restoring redox balance under sustained or complex stress conditions.

4.1.3. Redox regulation and lipid-derived mediators

Beyond antioxidant buffering and detoxification, Nrf2 regulates enzymes that fine-

tune redox-sensitive signaling networks, modulate inflammation through lipid mediators,

and safeguard proteostasis in cells under stress. These systems are particularly critical in

long-lived or non-dividing cells, including muscle fibers and neurons, where persistent

oxidative fluctuations can disrupt protein function and immune homeostasis.

A key component of Nrf2’s redox regulation is thioredoxin reductase 1 (TXNRD1),

which maintains thioredoxin in its reduced form, enabling it to reduce disulfide bonds in

proteins, thus repairing them, and ensuring redox signal fidelity.57,58 Superoxide

dismutases (SOD1–3), also under Nrf2 control, catalyze the dismutation of superoxide

radicals into hydrogen peroxide,

59 which a less reactive species subsequently detoxified by

catalase60 or glutathione peroxidase. These systems help maintain intracellular redox

gradients, allowing cells to sense and adapt to oxidative cues without triggering damage.

In addition, Nrf2 influences the metabolism of lipid-derived signaling molecules

through enzymes such as arachidonate 15-lipoxygenase (ALOX15). ALOX15 converts

polyunsaturated fatty acids into bioactive mediators like 15-HETE and lipoxins, which

resolve inflammation, promote macrophage polarization toward anti-inflammatory

phenotypes, and regulate redox-sensitive immune responses.61 This lipid signaling arm of

the Nrf2 pathway helps balance the inflammatory phase of stress responses with timely

resolution and tissue restoration.

To maintain proteostasis during oxidative stress, Nrf2 also upregulates genes

encoding specific proteasome subunits, enhancing both 20S and 26S proteasome activity.62

This supports the clearance of misfolded or oxidatively modified proteins, particularly

under conditions where autophagy is impaired or ATP is limited. The ATP-independent

20S core is especially crucial for degrading damaged proteins in energy-stressed cells. 63

Moreover, Nrf2 intersects with the cellular chaperone machinery to reinforce

proteome stability. It sustains redox conditions favorable for protein folding and

coordinates with heat shock proteins (HSPs) such as HSP70,64 assists in protein folding

and prevents aggregation under stress. HSP70 also activates activating transcription factor

4 (ATF4),65 a regulator of the integrated stress response that promotes survival and redox

balance. This redox–chaperone axis is particularly important in long-lived cells, such as

neurons, where oxidative injury can destabilize protein structure and impair cellular

function.66Through these interconnected pathways, which encompase redox signaling fidelity,

resolution-phase lipid mediators, and stress-adaptive protein quality control, Nrf2 equips

cells to withstand prolonged oxidative challenges without resorting to indiscriminate ROS

scavenging. These mechanisms are especially vital in sensitive tissues such as the nervous67

and cardiovascular68 systems, where maintaining structural and signaling integrity under

oxidative stress is essential for long-term cellular resilience.

4.1.4. Mitochondrial regulation

Nrf2 plays a pivotal role in preserving mitochondrial function during oxidative

stress by supporting transcriptional programs that regulate mitochondrial biogenesis, redox

homeostasis, and organelle quality control. These functions enable cells to sustain energy

production while minimizing mitochondrial-derived oxidative damage. One key axis

involves Nrf2’s regulation of peroxisome proliferator-activated receptor gamma

coactivator 1-alpha (PGC-1α), a master regulator of mitochondrial biogenesis. PGC-1α co-

activates nuclear respiratory factors (NRF1 and NRF2/GABPA),69 which promote the

expression of mitochondrial transcription factor A (TFAM)and other genes involved in

mitochondrial DNA replication and respiratory chain assembly.70 This coordination

supports mitochondrial renewal and metabolic flexibility in stress-challenged cells.

Under mild oxidative conditions, Nrf2 activity supports mitochondrial integrity by

enhancing the expression of enzymes such as SOD2 and GPX4, which are critical in

detoxifying mitochondrial ROS and preventing lipid peroxidation.71 It also works in

conjunction with redox-sensitive regulatory proteins like DJ-1 (PARK7), which stabilizes

Nrf2 by inhibiting its Keap1-mediated degradation and shields mitochondria from

oxidative injury.72 DJ-1 thus serves as a redox sentinel that bridges Nrf2 activity with

mitochondrial protection. This contributes not only to energetic resilience but also to redox

signal compartmentalization, enabling cells to respond proportionally to transient

mitochondrial stress.

Beyond antioxidant defense, Nrf2 influences mitochondrial quality control via

indirect crosstalk with AMP-activated protein kinase (AMPK) and autophagy pathways

(that will be elaborated upon later in this review). This includes modulation of mitophagy,

the selective degradation of damaged mitochondria, which prevents ROS leakage and

preserves metabolic homeostasis. In highly active and stress-sensitive tissues such as the

brain, heart, and liver, these pathways converge to align mitochondrial function with the

cell’s adaptive redox state.

Through these mechanisms, Nrf2 ensures that mitochondrial bioenergetics remain

resilient under oxidative stress, not only by protecting against damage but by actively

integrating mitochondrial health into the cell’s broader adaptive response network.4.1.5. Anti-Inflammatory and Cytoprotective Roles of Nrf2 73

Beyond its antioxidant and metabolic functions, Nrf2 plays a critical role in shaping

the immune response by modulating inflammation at the transcriptional level. Upon

activation, Nrf2 suppresses pro-inflammatory signaling pathways, notably nuclear factor

kappa B (NF-κB), and induces the expression of anti-inflammatory mediators that restore

immune balance.

Among its downstream targets, heme oxygenase-1 (HO-1) and ferritin serve dual

roles as antioxidant and immunoregulatory proteins. HO-1 not only degrades pro-oxidant

heme but also generates carbon monoxide and biliverdin, which exert anti-inflammatory

effects by inhibiting cytokine production and leukocyte recruitment. Ferritin sequesters

free iron, reducing oxidative inflammation and dampening tissue damage in inflammatory

processes.

Through these and related mechanisms, Nrf2 activation leads to the downregulation

of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β. This immune modulation

limits excessive inflammation, curtails immune cell hyperactivation, and preserves tissue

function across a range of pathological contexts, including:

• Autoimmune diseases: 74 Suppresses cytokine overproduction (so called

“cytokine storms”) and limits tissue injury in disorders such as lupus and multiple

sclerosis.

• Metabolic syndromes: 75 Attenuates chronic low-grade inflammation associated

with insulin resistance, diabetes, and obesity.

• Pulmonary disorders: 76 Mitigates airway inflammation in asthma, chronic

obstructive pulmonary disease (COPD), and acute lung injury.

• Neurodegenerative diseases: 77 Modulates microglial reactivity and reduces

neuroinflammation in conditions like Alzheimer’s and Parkinson’s disease.

By integrating redox regulation with immune restraint, Nrf2 acts as a central node in the

cytoprotective response to both oxidative and inflammatory stress. This dual role underpins

its emerging relevance in therapeutic strategies aimed at promoting resilience in redox-

sensitive tissues.

4.2. MAPK Signaling and Oxidative Stress Sensors

Beyond the Nrf2-Keap1 pathway, low level singlet oxygen can activate several

additional signaling pathways involved in stress response, inflammation regulation, cell

death and repair mechanisms. These pathways ensure that cells maintain homeostasis, limit

damage, and initiate adaptive processes during oxidative stress.

For example, the p53 tumor suppressor protein,78 a key regulator of DNA repair

and apoptosis, is activated in response to oxidative stress, helping cells manage or eliminatedamage. Similarly, the MAPK family consists of several key protein kinases, including

extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), and p38

MAPK, which are activated in response to various stress signals, including singlet oxygen.

It was found these kinases are activated through upstream stress sensors, including

oxidative modifications of receptor proteins, mitochondrial ROS signaling, and changes in

redox balance.79

These processes are critical for managing oxidative damage to DNA, lipids, and

proteins, and initiate appropriate adaptive or apoptotic responses depending on stress

intensity and duration.

4.3. Autophagy and Cell Fate Regulation

Singlet oxygen plays a complex and context-dependent role in cellular stress

responses, with the capacity to promote either cell survival or cell death. This duality is

mediated through its ability to induce autophagy or apoptosis, two distinct yet

interconnected processes that are often activated sequentially in response to stress.

Autophagy, a highly conserved mechanism present in all eukaryotes, from unicellular

organisms to mammals.

80 This mechanism is responsible for selectively degrading

oxidized and damaged intracellular components, such as proteins and organelles

(particularly mitochondria), via the lysosomal pathway. This process is essential for

preserving cellular integrity and function during mild stress.81

4.3.1. Oxidative Stress Intensity as a Determinant of Cell Fate

The outcome of oxidative stress is not binary but graded, depending on its intensity,

duration, and localization.35,82,83 At low to moderate levels, oxidative stress initiates

adaptive responses, including Nrf2 activation and the induction of autophagy, enabling

cells to restore homeostasis. In contrast, sustained or intense oxidative insults can

overwhelm these defenses, tipping the balance toward apoptosis or necrosis.

Importantly, singlet oxygen can directly oxidize signaling molecules that govern

this threshold. For example, it modifies cysteine residues on redox-sensitive kinases and

phosphatases, leading to the activation of ASK1, a MAP3K that mediates stress responses

including autophagy and apoptosis.84 Similarly, singlet oxygen promotes the disruption of

Bcl-2–Beclin-1 complexes via oxidative modifications of Bcl-2, releasing Beclin-1 and

enabling autophagy initiation.81,82,85

In addition, singlet oxygen can influence the hypoxia-inducible factor 1 (HIF-1)

pathway, which plays a pivotal role in cellular responses to low oxygen levels.86 While the

HIF-1 pathway is primarily known for regulating genes that adapt to hypoxic conditions,

it also intersects with autophagy mechanisms.These immediate oxidative modifications allow singlet oxygen to act as a first

messenger in stress adaptation, influencing the balance between repair and cell death

independently of transcription. This reinforces the concept of oxidative stress as a rheostat,

where controlled oxidation promotes survival pathways, while excess shifts the balance

toward irreversible damage.

4.3.2. Subtypes of Autophagy

The primary forms of autophagy implicated are macroautophagy, mitophagy, and

chaperone-mediated autophagy (CMA), each targeting distinct cellular liabilities within

the cell.

Macroautophagy (often just referred to as autophagy) is responsible for bulk

degradation of damaged or oxidized cytoplasmic material. Upon low-level oxidative stress,

singlet oxygen can trigger macroautophagy by oxidizing redox-sensitive regulators,

enabling the sequestration of dysfunctional proteins and organelles into autophagosomes.

Although traditionally viewed as non-selective, macroautophagy often targets specific

substrates based on oxidative modification patterns.81,87

Mitophagy, a specialized subset of macroautophagy, mitophagy, specifically

eliminates damaged or dysfunctional mitochondria. Mitochondria are central to cellular

energy production. However, as organisms age, mitochondrial DNA (mtDNA)

accumulates mutations, leading to decreased efficiency in the electron transport chain and

increased production of ROS. The increased oxidative stress may further damage cellular

components, thus accelerating aging and age-related diseases,88 including

neurodegenerative disorders,

89 cardiovascular diseases, 90 and metabolic syndromes91

. This

underscores the importance of inducing mitophagy to remove these compromised

organelles and prevent further ROS production. Two mitophagy pathways have been

identified. In one pathway, JNK influences mitophagy through the modulation of

PINK1/Parkin Pathway, as JNK activation can promote the stabilization of PINK1 on the

outer membrane of depolarized mitochondria, facilitating the recruitment of Parkin, an E3

ubiquitin ligase. Parkin ubiquitinates mitochondrial proteins, marking the mitochondria for

autophagic degradation.92

Independently of the PINK/Parkin pathway, mitophagy can also occur through the

phosphorylation of FUNDC1.

93 JNK phosphorylates FUNDC1, a mitochondrial receptor,

which enhances its binding affinity for LC3 or other autophagy proteins, facilitating the

engulfment of damaged mitochondria by autophagosomes.Chaperone-Mediated Autophagy (CMA)94isa form of autophagy that

selectively degrades soluble cytosolic proteins containing the KFERQ-like pentapeptide

motif. Under oxidative stress, oxidized proteins are recognized by chaperones and

translocated directly into lysosomes for degradation. This process helps in the removal of

oxidatively damaged proteins, thereby maintaining protein quality control.95 JNK signaling

has been implicated in modulating this pathway as it may influence the expression of

chaperone proteins under mild oxidative conditions, thereby enhancing the selective

degradation of oxidized cytosolic proteins. While the direct involvement of JNK in CMA

regulation is less clear, oxidative stress may upregulate the expression of LAMP-2A,96 the

lysosomal receptor essential for CMA substrate translocation. Increased LAMP-2A levels

enhance the cell’s capacity to degrade oxidized proteins via CMA.97 In addition, stress

conditions can affect the activity of Hsc70,94 the cytosolic chaperone that recognizes and

delivers substrates to LAMP-2A. Modulation of Hsc70 activity influences the efficiency

of CMA.

Together, these autophagic pathways offer an orchestrated response that favors

selective clearance and functional recovery rather than indiscriminate degradation, a

hallmark of the hormetic action of singlet oxygen.

4.3.3. Biological Implications of Autophagy

Autophagy pathway activation has been shown to prevent stress-induced tissue and

organ injury. Beyond its immediate cytoprotective function, autophagy contributes to a

wide range of systemic adaptations relevant to stress resilience, aging, immunity, and tissue

homeostasis.

4.3.3.1. Systemic Functions: Immunity, Inflammation, and Aging

Autophagy plays a multifaceted role in immune homeostasis. It mitigates chronic

inflammation by degrading damaged organelles and oxidized macromolecules, thereby

limiting the passive release of damage-associated molecular patterns (DAMPs)98 such as

mitochondrial DNA, ATP, and oxidized proteins. This suppression of DAMP leakage helps

prevent uncontrolled inflammasome activation and cytokine release. Conversely, under

certain stress conditions, autophagy may also actively facilitate the secretion of select

DAMPs, such as HMGB1, through non-classical pathways- initiating a context-dependent

immunomodulatory feedback loop that can further enhance autophagy.99

In addition, autophagy functions as a key regulator of immune responses. It plays a

crucial role in defending against intracellular pathogens by sequestering and degrading

them through a process known as xenophagy,

100 as well as contributing to antigenprocessing and presentation via MHC class II molecules, supports T cell development and

homeostasis, and helps shape adaptive immune responses.

Through these mechanisms, autophagy serves as a multi-layered system that

integrates microbial defense, inflammation control, and immune regulation, highlighting

its potential as a therapeutic target for infectious, inflammatory, and autoimmune

diseases.101

In the aging context, basal autophagy levels decline, contributing to the

accumulation of cellular damage. Mild oxidative signals such as singlet oxygen can act as

hormetic triggers to transiently restore autophagic activity, improving stress resistance and

supporting tissue regeneration.102 Autophagy also preserves stem cell function across

multiple tissues, including muscle, liver, and hematopoietic systems, by maintaining redox

and mitochondrial integrity.103

4.3.3.2. Nervous System: Maintaining Proteostasis and Synaptic

Health

Neuronal cells are especially vulnerable to oxidative damage due to their high

metabolic demands and limited regenerative capacity. Autophagy helps remove

dysfunctional mitochondria (mitophagy) and protein aggregates, maintaining proteostasis

and preventing excitotoxicity. In the context of singlet oxygen exposure, selective

autophagy helps prevent the accumulation of neurotoxic proteins such as α-synuclein and

phosphorylated tau, processes implicated in neurodegenerative diseases104,105 including

Parkinson’s and Alzheimer’s106

. Moreover, autophagy contributes to neural development

and synaptic plasticity, influencing learning and memory processes.105 Dysregulation of

autophagy with aging or chronic oxidative stress can exacerbate excitotoxicity and synaptic

loss, while controlled activation may confer neuroprotection.107

4.3.3.3. Skin: Barrier Maintenance and Oxidative Detoxification

The skin can be viewed as a dynamic immuno-cutaneous ecosystem, where

autophagy within skin cells plays a crucial role in preserving immune balance. 108 As the

body’s largest interface with the environment, the skin is chronically exposed to

environmental stressors such as ultraviolet (UV) radiation, pathogens, and oxidants,

stressors that can damage keratinocytes, lipids, and extracellular matrix proteins.

Autophagy plays a central role in removing harmful intracellular components, maintain

cellular homeostasis, and prevent inflammation and premature aging.109

A wide range of resident immune cells inhabit the skin, including Langerhans cells,

dermal dendritic cells, macrophages, mast cells, and tissue-resident T cells. These immunecells are in ongoing communication with keratinocytes and other structural cells of the

skin, collaboratively detecting and responding to pathogens, tumors, allergens, and

autoantigens through intercellular signaling involving DAMPs and pathogen-associated

molecular patterns (PAMPs) 110

.

• Keratinocytes, the predominant cells of the epidermis, are particularly active

in this process. In response to UV exposure, oxidative stress, or physical injury,

they release DAMPs such as HMGB1, ATP, IL-1α, uric acid, and heat shock

proteins. They also express pattern recognition receptors (PRRs), including

Toll-like receptors (TLRs) and NOD-like receptors,111 to identify microbial

PAMPs like bacterial lipopolysaccharide (LPS), viral RNA, or fungal β-

glucans.110

• Dermal fibroblasts also serve as key immune modulators. They detect both

DAMPs and PAMPs in response to tissue stress, contributing to immune cell

recruitment and activation. Importantly, fibroblasts exhibit considerable

heterogeneity, with specific subpopulations involved in immune surveillance,

epithelial–immune cell communication and sustaining chronic skin

inflammation.

112

• Melanocytes, while less studied in this context, can respond to PAMPs by

producing cytokines and chemokines, and may also release DAMPs under

oxidative stress, a process implicated in inflammatory skin conditions such as

vitiligo.

113

It has been shown that autophagy supports the function of key skin cells types,

including keratinocytes, melanocytes, and immune cells, by regulating inflammation,

promoting cell differentiation, and protecting against infection. In dermal fibroblasts,

autophagy plays a critical role in modulating responses to DAMPs and PAMPs, limiting

excessive immune activation through the degradation of damaged organelles and the

regulation of cytokine release.112 In keratinocytes and epidermal stem cells, autophagy

helps preserve skin renewal and barrier function, thereby reducing pathogen penetration

and lowering the activation threshold of resident immune cells. In melanocytes, autophagy

contributes to pigmentation homeostasis by regulating melanin distribution.

114

These functions highlight autophagy’s essential role in skin wound healing across

all key phases: hemostasis, inflammation, proliferation, and remodeling.115 It promotes

keratinocyte proliferation and migration, drives fibroblast activation and differentiation,

supports new blood vessel formation (angiogenesis), and helps clear damaged organelles

and inflammatory mediators, supporting efficient tissue repair and re-epithelialization.

Additionally, autophagy contributes to immune balance by regulating macrophage and

neutrophil activity and supporting resolution of inflammation.

When autophagy is disrupted, it can lead to cellular senescence, chronic

inflammation, impaired wound healing, and increased risk of pathological scarring or skincancers. Dysregulated autophagy is also associated with immune-related skin disorders,

including atopic dermatitis, psoriasis, and alopecia areata. 108

It can be concluded that the controlled induction of autophagy may offer a more

effective, targeted approach for managing chronic skin conditions. It is also a promising

therapeutic target for enhancing wound healing outcomes, treating skin aging and related

disorders.

4.3.3.4. Lung: Adaptive Remodeling and Inflammation Control

Autophagy plays a multifaceted role in lung injury and repair by supporting tissue-

specific responses such as alveolar regeneration, redox homeostasis, and immune

modulation. In particular, autophagy is essential for alveolar type 2 (AT2) progenitor cell–

mediated regeneration following lung injury.116 By promoting glucose, limiting lipid

accumulation, and reducing oxidative stress, autophagy supports AT2 proliferation and

epithelial barrier restoration.

In acute lung injury (ALI), autophagy interacts with the Nrf2 Nrf2 pathway to

enhance antioxidant defense:117 by degrading the Nrf2 inhibitor Keap1, autophagy

facilitates Nrf2 stabilization, contributing to protection against oxidative inflammation and

preserving alveolar function. However, as in other tissues, the context and extent of

autophagy determine its protective vs. detrimental effects

This balance becomes especially relevant in sepsis-induced lung injury, where

autophagy maintains epithelial barrier integrity and regulates immune cell activity.

Excessive or prolonged autophagic activation under systemic inflammatory stress may

contribute to tissue damage and impaired resolution.

118

Autophagy also contributes to the pathogenesis of chronic pulmonary diseases:

• In chronic obstructive pulmonary disease (COPD), impaired autophagy disrupts

mitochondrial clearance, while excessive autophagy can lead to epithelial cell

death and persistent inflammation. Both patterns contribute to tissue destruction

and reduced regenerative potential. 119,120

• In idiopathic pulmonary fibrosis (IPF), deregulated autophagy in epithelial and

mesenchymal cells is associated with aberrant fibroblast activation and

extracellular matrix accumulation, promoting fibrosis. 121,122

• In asthma, autophagy modulates immune cell recruitment and cytokine release,

influencing airway inflammation and remodeling. Dysregulated autophagy has

been linked to enhanced airway hyperresponsiveness and resistance to

corticosteroids. 119,123Taken together, these findings underscore the context-dependent roles of autophagy

in pulmonary health. Targeting autophagic signaling in a cell-type- and disease-specific

manner may open new therapeutic avenues for both acute and chronic lung diseases.

4.3.3.5. Cardiovascular System: Cardioprotection and Vascular

Homeostasis

Autophagy plays a critical role in maintaining cardiovascular health by supporting

the turnover of damaged cellular components, particularly under stress conditions such as

ischemia.124 In cardiac tissues, this process reduces myocardial injury, facilitates tissue

remodeling, and promotes recovery after oxidative or mechanical insults. 138

When autophagy is defective or insufficient, cardiomyocytes accumulate

dysfunctional mitochondria, misfolded proteins, and oxidative byproducts,

125 which are

hallmarks of cardiac aging and pathology. These impairments contribute to the progression

of cardiomyopathies and heart failure. Mitophagy, the targeted removal of damaged

mitochondria, is especially vital in the heart, where cells contain a high density of

mitochondria and are constantly subjected to high oxidative and metabolic demands. By

clearing depolarized mitochondria, mitophagy limits excessive ROS production and

protects against ischemia–reperfusion injury. 126

In the vascular system, autophagy also serves as a key homeostatic mechanism.

Endothelial cells rely on basal autophagic activity to preserve nitric oxide signaling, limit

vascular inflammation, and prevent atherogenesis. When this regulatory process is

impaired, either by aging, chronic inflammation, or external oxidative stimuli such as

singlet oxygen, vascular dysfunction and pro-atherogenic changes may ensue. 124

Importantly, the Nrf2–autophagy axis integrates redox-sensitive signaling with

lipid metabolism and immune regulation, offering an additional layer of protection against

oxidative and inflammatory stressors. Through this pathway, low-level singlet oxygen may

promote adaptive remodeling and preserve vascular tone without triggering damaging

oxidative overload. 127

Together, these findings position autophagy as a central mechanism in

cardiovascular resilience, mediating both cardiac and vascular adaptations to oxidative

stress, including that induced by singlet oxygen exposure.

4.3.3.6. Skeletal Muscle: Quality Control and Adaptation to Stress

Autophagy maintains skeletal muscle homeostasis by removing dysfunctional

proteins and organelles, particularly mitochondria, which is essential for preserving muscle

mass, contractile performance, and metabolic adaptability. Mitophagy, the selectivedegradation of damaged mitochondria, plays a particularly critical role in muscle fibers,

where high oxidative load and metabolic turnover necessitate constant mitochondrial

quality control. Impairments in this process have been associated with various myopathies,

including sarcopenia, muscular dystrophies, and cancer-associated cachexia, as

accumulation of dysfunctional mitochondria and protein aggregates leads to fiber atrophy

and impaired regeneration.128,129

During physiological stress such as endurance exercise or caloric restriction,

autophagy is transiently upregulated to promote muscle fiber remodeling, improve

mitochondrial efficiency, and mobilize intracellular substrates for energy production. This

dynamic regulation involves key redox-sensitive signaling hubs, including AMPK and the

Nrf2 pathway, which coordinate the transcriptional and post-translational activation of

autophagy machinery in response to oxidative fluctuations.130 Notably, exercise-induced

production of singlet oxygen and other reactive oxygen species may act as a hormetic

trigger to fine-tune autophagic activity, enhancing long-term muscle resilience and

metabolic health. Understanding the precise balance of autophagic signaling in skeletal

muscle may therefore hold therapeutic relevance for age-related muscle decline and

metabolic syndromes.

4.3.3.7. Endocrine System: Hormone Regulation and Organelle

Turnover

Within endocrine tissues, autophagy plays a dual role in general cellular

maintenance and in regulating hormone synthesis and secretion. In peptide-producing cells

such as those of the pituitary gland, a specialized autophagic process known as crinophagy

enables the degradation of excess secretory granules, thus preventing hormone

hypersecretion and contributing to hormonal balance. 131

In steroidogenic cells of the adrenal cortex and testes, autophagy selectively targets

mitochondria and smooth endoplasmic reticulum, which are organelles central to steroid

biosynthesis. This regulatory role ensures metabolic efficiency and prevents oxidative

damage, especially under stress conditions.132

Additionally, autophagy in endocrine tissues is modulated by oxidative signals,

including ROS such as singlet oxygen, which can trigger redox-sensitive autophagy

pathways to adjust hormonal output. Dysfunctional autophagy in endocrine glands has

been associated with various pathologies, including diabetes, infertility, and hormone-

secreting tumors, due to disrupted secretory or steroidogenic functions.132,133

These findings suggest that targeted modulation of autophagy in endocrine tissues

could represent a novel therapeutic approach to hormone-related disorders and metabolic

diseases.4.3.3.8. Pregnancy: Placental Development and Immune

Tolerance134

Autophagy plays a vital role in pregnancy by regulating trophoblast survival,

supporting placental development, maintaining immune tolerance, and adapting to the

dynamic metabolic demands of both mother and fetus. During early gestation, trophoblasts

invade the uterine lining under low-oxygen conditions; here, autophagy facilitates cellular

survival and promotes cytotrophoblast differentiation into the invasive phenotype essential

for placental formation.

Autophagy also contributes to maternal–fetal immune tolerance by modulating

inflammatory cytokine signaling, promoting tolerogenic dendritic cells, and regulating T

cell activation. These effects reduce the risk of immune-mediated rejection of the semi-

allogeneic fetus and help maintain immunological equilibrium at the maternal-fetal

interface. 135

Additionally, under periods of maternal nutritional stress, autophagy enables

intracellular recycling of macromolecules to maintain fetal nutrient supply and energy

balance. Dysregulated autophagy, whether insufficient or excessive, has been implicated

in various pregnancy complications, including preeclampsia, intrauterine growth

restriction (IUGR), and gestational diabetes mellitus (GDM), highlighting its protective

function in sustaining placental and fetal health. 136

4.3.3.9. Liver: Metabolic Regulation and Tissue Regeneration

The liver relies on autophagy for maintaining metabolic balance, detoxification,

and redox homeostasis. 129,137 Through lipophagy, autophagy facilitates the degradation of

intracellular lipid droplets, contributing to lipid turnover and preventing hepatic steatosis.

Simultaneously, mitophagy ensures the removal of dysfunctional mitochondria, protecting

hepatocytes from oxidative stress and limiting ROS production. This mitochondrial quality

control also supports energy-efficient regeneration of liver tissue following injury,

ensuring adequate ATP production while minimizing oxidative damage.129,138

Dysregulation of hepatic autophagy has been implicated in liver diseases such as non-

alcoholic fatty liver disease (NAFLD), alcoholic hepatitis, and fibrosis, underscoring its

critical role in hepatocellular protection and regeneration.139

4.3.4. Concluding Synthesis: Autophagy as a Hormetic Mediator of

Singlet Oxygen Signaling

Across a wide spectrum of tissues and physiological systems, autophagy emerges

as a central regulatory process that integrates metabolic signals, oxidative cues, and stress

adaptation. The evidence compiled in this chapter reveals a unifying theme: low-level

oxidative stress, particularly that induced by singlet oxygen, can serve as a hormeticstimulus, activating autophagic pathways that support cellular renewal, immune

modulation, and tissue repair.

In barrier tissues such as the skin and lungs, autophagy preserves epithelial

integrity, controls inflammation, and enhances resilience to environmental insults. In

skeletal and cardiac muscle, it maintains mitochondrial quality and metabolic homeostasis,

particularly during physiological challenges like exercise or ischemia. In the liver, it

coordinates lipid turnover and regeneration, while in the endocrine system and placenta,

autophagy modulates hormonal synthesis and immune tolerance. Even during pregnancy,

autophagy protects the maternal-fetal interface and contributes to placental development.

These diverse functions are governed by overlapping molecular mechanisms,

including mitophagy, lipophagy, and redox-sensitive signaling via Nrf2, AMPK, and

mTOR, yet are finely tuned to the needs of each tissue context. The dual role of autophagy

in both cytoprotection and cell death is especially notable: the intensity and duration of

singlet oxygen exposure may dictate whether autophagy serves a survival-promoting or

pathological role, reflecting the delicate threshold between adaptive and maladaptive

responses.

Understanding this context-dependence and threshold sensitivity is crucial for

therapeutic modulation. Pharmacological or photo-induced activation of singlet oxygen

may, under controlled conditions, be harnessed to stimulate beneficial autophagy, offering

novel treatment avenues in inflammatory, degenerative, metabolic, and fibrotic diseases.

In summary, autophagy is not merely a stress response- it is a homeostatic amplifier

of hormetic signaling. Through its ability to decode singlet oxygen cues into tissue-specific

adaptive programs, autophagy bridges environmental sensing with intracellular resilience,

affirming its relevance as both a biomarker and target of oxidative medicine.

5. Temporal dynamics of oxidative stress response

The adaptations to oxidative stress unfold in a time-dependent manner83 and can

result in long-lasting physiological benefits (Table 2). Early after oxidative insult, typically

within minutes, NF-κB is rapidly activated, leading to a transient pro-inflammatory

response that primes the system for defense and cellular recruitment.

140 Within 1–3 hours,

these early signals stimulate transcriptional programs, notably via Nrf2, promoting

transcription of phase II detoxification enzymes and antioxidant defenses, such as HO-1

and NQO1. As these protective proteins accumulate, they provide an enhanced state of

stress resilience lasting up to 48 hours.

83,141,142Table 2 Timing and duration of defence responses to moderate oxidative stress83,140-142

Response Type Trigger Onset (Approx.) Duration

NF-κB

ROS Minutes 1–3 hours

activation

Nrf2

4-HNE,

1–3 hours activation

ROS

6–48 hours

(longer term)

Autophagy

Persistent

Several

Long-lasting

induction

ROS

hours

(days)

Cellular

Nrf2/ARE

After Nrf2

Hours–days

repair

genes

signal

During this intermediate phase, lipid peroxidation by-products like 4-

hydroxynonenal (4-HNE) act as secondary messengers that stably modify proteins and

influence cell signaling well beyond the initial oxidative event.141 This extended adaptive

phase is further supported by the induction of autophagy, typically induced several hours

after exposure, contributing to cellular maintenance by clearing damaged organelles.

140

These processes are complemented by cellular repair mechanisms, activated to restore

redox balance and tissue integrity.

Together, these temporally orchestrated responses to moderate oxidative stress,

such as that induced by singlet oxygen, foster a sustained hormetic effect that contributes

to cellular preconditioning, enhanced metabolic regulation, and long-term resilience to

stress

The preceding sections have outlined the dual nature of singlet oxygen and its

capacity to activate adaptive stress responses, enhance mitochondrial function, and

modulate immune and redox signalling pathways when delivered at low, sub-toxic

concentrations. These mechanistic insights support the biological plausibility of

therapeutic benefits observed under controlled oxidative exposure. In this context,

preliminary clinical observations, including case reports and practitioner experiences,

suggest that low-level ambient singlet oxygen exposure may be associated with measurable

improvements in diverse physiological domains, including respiratory function,

hematopoiesis, immune regulation, and neurobehavioral responses. Although these reports

are observational and uncontrolled, they offer physiologically plausible insights that are

broadly consistent with the hormetic and redox-mediated processes described in earlier

sections. However, these findings should be interpreted cautiously and underscore the need

for systematic clinical validation. This section presents a summary of selected individual

patient reports and clinical observations describing subjective or objective functional

improvements following low-dose Singlet Oxygen Therapy (SOT), administered via a

patented device that generates low-dose singlet oxygen without irradiation.185.1. Effects on Sleep Quality and Sleep Disorders

One of the earliest and most consistently reported effects by individuals undergoing

SOT, including both healthy subjects and those with chronic conditions, is a subjective

improvement in sleep quality. These improvements include reports of faster sleep onset,

longer uninterrupted sleep, and fewer nocturnal awakenings. Such effects are notable given

the central role sleep plays in physiological repair, cognitive functioning, and immune

modulation.143

Sleep is closely tied to redox biology.144 During restful sleep, antioxidant systems

are restored, and metabolic byproducts, including ROS, are effectively neutralized.

Conversely, sleep deprivation has been shown to elevate oxidative stress in the brain and

peripheral tissues, disrupt redox-sensitive signaling pathways,145 and increase the

production of pro-inflammatory cytokines such as TNF-α and IL-6. These inflammatory

mediators can also impair sleep regulation, potentially reinforcing a feedback loop of

oxidative stress, immune dysregulation,143 and poor restorative capacity146

. This may

contribute to increased risk for chronic diseases such as cardiovascular and

neurodegenerative disorders.147

Clinical Case 1: Remission of Obstructive Sleep Apnea Without CPAP

A 69-year-old male diagnosed with mild-to-moderate obstructive sleep apnea

(OSA) in 2018 (AHI 7.0; SpO₂ nadir 86%) was unable to tolerate continuous positive

airway pressure (CPAP) therapy. Beginning in 2020–2021, he initiated nightly use of a

passive, low-dose singlet oxygen-emitting device during sleep. Over the following years,

he experienced a reported improvement in sleep quality and energy, coinciding with

modest weight loss (BMI decreased from ~29 to 24.7).

A follow-up sleep study in 2025 revealed normalized breathing parameters (AHI

6.8, mean SpO₂ 93%, nadir 87%, sleep efficiency 91.4%), and CPAP was deemed

unnecessary. Although causality cannot be established, the temporal association raises the

possibility that SOT contributed to improved upper airway function and respiratory

stability during sleep. This represents a rare instance of OSA remission without CPAP,

surgery, or pharmacological intervention.

Proposed Mechanisms: Evidence from preclinical and clinical studies suggests that

moderate, transient oxidative stimuli, such as those induced by singlet oxygen, can restore

redox balance through hormetic mechanisms that recalibrate circadian rhythms148 and

stress responses. This may include the resetting of dysfunctional sleep-wake cycles and

attenuation of hyperarousal states commonly associated with insomnia and anxiety.

149,150Users commonly describe experiencing noticeable improvements within the first

24 hours of singlet oxygen exposure. These rapid effects may reflect immediate

neurophysiological adaptations via redox-sensitive systems involved in melatonin

synthesis, hypothalamic signaling, or neuronal hyperexcitability.151 While speculative, the

observed restoration of sleep continuity may suggest an indirect role for singlet oxygen in

modulating neuroimmune interactions152 and systemic stress resilience.

5.2. Snoring alleviation

Snoring and sleep-disordered breathing are widespread issues, affecting over 40%

of the population at some point in their lives with varying severity. These conditions disrupt

sleep architecture by limiting airflow and preventing entry into deeper, restorative sleep

phases. Snoring typically results from partial obstruction of the upper airway, often due to

relaxed throat muscles, excess soft tissue, nasal congestion, or tongue positioning, leading

to vibratory noise as air passes through narrowed passages.

In otherwise healthy individuals, snoring may present as a benign nuisance,

typically impacting bed partners. However, in more severe presentations such as

obstructive sleep apnea (OSA) or asthma, repeated airway collapse can result in

intermittent hypoxia, oxidative stress, and increased cardiovascular and metabolic risks. 153

Clinical Observations: Passive Snoring Reduction in Bed Partners

Anecdotal reports from users ofSOThave described significant reductions in

snoring frequency and intensity, including among individuals not directly using the device.

In over 90 reported cases, individuals receiving SOT for unrelated conditions, noted that

their bed partners, many of whom were habitual snorers, experienced diminished or absent

snoring during the treatment period.

One particularly striking case involved an asthma patient who began nightly SOT;

shortly thereafter, his wife, previously a consistent snorer, ceased snoring entirely. This

effect occurred without her direct use of the device, raising the possibility that passive

exposure to singlet oxygen-enriched air may influence upper airway function.

Proposed Mechanisms: Several biological mechanisms could plausibly explain these

effects. Low-level oxidative stress induced by singlet oxygen may elicit hormetic responses

that promote subtle increases in upper airway muscle tone,154 thereby reducing the

likelihood of collapse during sleep. It may also attenuate inflammation, a key contributor

to airway narrowing in conditions such as allergic rhinitis and sinus congestion. Given that

OSA and snoring are associated with chronic inflammation and oxidative stress in theupper airway, the redox-balancing effects of singlet oxygen may help reduce tissue

swelling, improve airflow, and lower snoring severity.

While these observations are mechanistically consistent with findings described in

Sections 5 and 7, they remain preliminary. Controlled clinical studies are needed to

determine the extent and reproducibility of SOT’s impact on snoring and upper airway

physiology.

5.3. Alleviation of Chronic Nightmares and Post-Traumatic Stress Symptoms

Chronic nightmares, that are distressing, recurrent dreams that disrupt sleep, affect

approximately 2–6% of adults and are especially common in individuals with post-

traumatic stress disorder (PTSD), anxiety, or depression.155 Despite their impact on sleep

quality and mental health, nightmares are frequently underdiagnosed and undertreated.

They are rarely spontaneously reported by patients and often overlooked by clinicians,

despite well-documented associations with increased risk of suicide, insomnia, and

emotional dysregulation.156,157 This persistent clinical neglect has contributed to diagnostic

and therapeutic gaps, leaving many individuals untreated despite significant sleep

disruption and psychological distress.

Clinical Case: Resolution of Trauma-Associated Nightmares Following SOT

A woman who experienced daily trauma-related nightmares for eight years

following an intraoperative awareness event reported immediate and lasting resolution of

her symptoms after beginning SOT. Her symptoms, including dissociative aftereffects,

reportedly ceased within the first nights of exposure, enabling sustained sleep restoration

for the first time in years.

Proposed Mechanisms: These effects may be mediated by redox-sensitive neural

pathways involved in fear processing and REM regulation. Singlet oxygen-induced low-

level oxidative stress may activate antioxidant and anti-inflammatory responses in limbic

structures such as the amygdala and prefrontal cortex. These adaptations could stabilize

neural activity and reduce hyperarousal, thereby improving REM sleep continuity and

reducing nightmare intensity.158

Although mechanistically plausible and consistent with preclinical literature on

redox-neural interactions, these observations remain anecdotal. Controlled studies are

required to confirm therapeutic efficacy in nightmare disorders or trauma-related sleep

disturbances.

5.4. Enhancing Exercise Recovery and Performance

A recent study by Hsieh et al.

159 reported enhanced exercise performance and

physiological resilience following exposure to low-dose singlet oxygen energy (SOE).Participants using a passive, non-invasive singlet oxygen-generating device during

exercise showed improvements in cardiorespiratory function, muscle recovery, and

subjective vitality.

Rather than attributing these effects solely to SOE, as the writers do, they may

reflect generalizable redox-based mechanisms consistent with known physiological

adaptations to exercise. Physical activity induces transient oxidative stress that activates

hormetic signaling pathways, including Nrf2-mediated antioxidant responses160 and

mitochondrial biogenesis via AMPK and PGC-1α.161 These responses are part of

mitohormesis, a process by which low-level mitochondrial stress improves energy

metabolism, mitochondrial quality control (via fusion/fission and mitophagy), and

resistance to subsequent challenges.162

During recovery, moderate ROS exposure stimulates AMPK signaling, facilitating

glucose uptake, fatty acid oxidation, and mitochondrial renewal via upregulation of PGC-

1α.163 In parallel, increased expression of antioxidant enzymes, such as superoxide

dismutase and heme oxygenase-1, mitigates inflammation and protects muscle tissue from

oxidative damage.164 These established processes likely underlie the recovery-related

benefits observed by Hsieh et al.

Thus, while the SOE device appears to confer tangible benefits, these

improvements are interpretable within the broader framework of redox-based adaptive

physiology, as discussed in Sections 5 and 7. Future studies comparing singlet oxygen-

based delivery to other hormetic interventions, using biomarkers and controlled exercise

protocols—could provide a clearer understanding of its relative efficacy.

5.5. Impact on Respiratory Health: Asthma, COPD, and Airway Inflammation

5.5.1. Asthma

Asthma is a chronic inflammatory airway disease characterized by bronchial

hyperresponsiveness, reversible airway obstruction, and recurrent symptoms such as

wheezing, coughing, and breathlessness. Common triggers include allergens, exercise,

infections, and environmental irritants. During exacerbations, airway inflammation leads

to bronchial constriction, edema, and mucus production, reducing airflow and impairing

gas exchange.165

Repeated asthma attacks increase the risk of airway remodeling and irreversible

airflow limitation. Conventional therapies, including corticosteroids and bronchodilators,

are effective but often carry side effects, and many patients remain symptomatic despite

optimized pharmacological management.166 Therefore, there is a growing interest inadjunctive therapies aimed at reducing attack frequency, minimizing reliance on synthetic

drugs, and enhancing endogenous healing responses.

Observational Reports of Singlet Oxygen Therapy in Asthma

Self-reported observations suggest that singlet oxygen-enriched air may confer

both acute relief and longer-term benefits for asthma patients. Users have described rapid

alleviation of breathlessness during attacks, as well as a gradual reduction in attack

frequency and medication dependence. Notably, several individuals who previously

required prophylactic steroids for seasonal asthma reported discontinuing their medication

after consistent nightly SOT. Some also reported improvements in symptoms associated

with airway remodeling.

Preliminary Clinical Study

In a small observational study conducted in Spain by Prof. M. Fegricio,167 two

groups of 25 asthma patients were evaluated over 30 and 60 days. The treatment group

used a low-level ambient singlet oxygen generator daily, while the control group received

a sham device. Patient-reported outcomes (Error! Reference source not found.) showed

significant improvements in sleep quality and energy in the treatment group, alongside a

reduction in weekly asthma attacks (from 1.08 to 0.48 attacks/week). Sixteen patients

discontinued all pharmacologic treatment by the study’s end, while no such changes

occurred in the control group.

Figure 4 Change in the average rating of energy levels and sleep quality of 25 asthma patients, with (left graph) and

without (right graph) daily usage of low-level ambient singlet oxygen generator over a period of 60 days.167

Proposed Mechanisms: While preliminary and based on observational data, these

findings are consistent with the mechanistic rationale discussed in Sections 5 and 7.

Specifically, the controlled oxidative signal generated by singlet oxygen may activateredox-sensitive anti-inflammatory and epithelial repair pathways. These processes could

improve airway tone and mucosal integrity, thereby lowering susceptibility to

bronchoconstriction. However, controlled trials are essential to validate these effects and

rule out placebo influences or seasonal fluctuations.

5.5.2. Chronic obstructive pulmonary disease (COPD)

Chronic obstructive pulmonary disease (COPD), a progressive respiratory disorder

encompassing chronic bronchitis and emphysema, is characterized by persistent airflow

limitation, mucus overproduction, and alveolar destruction. As the third leading cause of

death in the United States,168 COPD currently has no cure, only supportive treatments are

available, aimed at slowing disease progression and managing symptoms.

Patients with advanced COPD often experience debilitating breathlessness,

frequent exacerbations, and, eventually, dependence on supplemental oxygen. Without a

lung transplant, this condition ultimately proves fatal. In this context, low-level singlet

oxygen exposure has been anecdotally associated with perceived improvements in

breathing and function.

Several users have reported enhanced respiratory ease and a reduction in oxygen

dependence within days of initiating therapy. A few individuals with advanced disease

described regaining the ability to work and travel, improvements that warrant systematic

investigation. In some cases, spirometry conducted after a month of use revealed increases

in forced expiratory volume (FEV₁) and improved FEV₁/FVC ratios, outcomes not

commonly observed in late-stage COPD with non-invasive methods.

These preliminary findings align with earlier observational reports, such as a small,

unpublished study in which patients with moderate-to-severe COPD underwent a four-

week regimen of singlet oxygen inhalation therapy.169 Participants demonstrated modest

improvements in FEV₁, peak expiratory flow, and a reduction in symptom burden and

bronchodilator use. Although the study lacked a control group and peer review, its

outcomes parallel known physiological mechanisms described in Sections 5 and 7,

including redox-modulated inflammation control, epithelial repair, and enhanced

mitochondrial turnover.The following case reports provide individual examples of patients with moderate

to severe COPD who reported respiratory improvements following routine use of SOT.

Clinical Case 1: Functional and Spirometric Improvement in a Patient with Severe

COPD Following SOT

A 67-year-old male with a 20-year smoking history (approx. 1 pack/day) was

diagnosed with severe COPD. Despite smoking cessation, his respiratory condition

progressively worsened, with persistent wheezing, dyspnea, and pulmonary congestion that

impaired basic activities such as walking and showering.

Initial treatment included corticosteroids (prednisone) and antibiotics (cephalexin),

though his lung function continued to deteriorate. FEV₁ declined from 52% to 35%

predicted within a year. At this point, physicians recommended long-term oxygen therapy

and pulmonary rehabilitation. In April 2017, the patient initiated daily SOT. Within days,

he reported subjective improvement in breathing and energy levels. Over the following

weeks, he resumed travel and returned to work. Spirometry one month into therapy

indicated an increase in FEV₁ from 35% to 58% predicted, with further improvement (63%)

over the next year. No changes in standard medications were recorded during this time.

Although causality cannot be established from a single case, the timing and

magnitude of improvement support further investigation into singlet oxygen as a potential

adjunct therapy in COPD management.

Clinical Case 2: Remission of COPD With Discontinuation of Inhaled Therapy

Following Passive Singlet Oxygen Exposure

A 57-year-old female with heavy smoking history was diagnosed in 2020 with

moderate COPD, confirmed by spirometry (FEV₁ ~83%; FEV₁/FVC <80%). She

experienced progressive dyspnea, wheezing, and exertional fatigue that interfered with her

occupation as a children’s entertainer.

In 2021, the patient began nightly SOT. During the first week, she experienced

productive coughing with green sputum, possibly reflecting a mucolytic or detoxification

response. Over the next two months, she noted substantial improvements in breathing and

physical stamina. Wheezing fully resolved within three months. Initially prescribed four

inhaled medications, including corticosteroids and bronchodilators, the patient gradually

discontinued them over a six-month period. By year’s end, she remained asymptomatic

and off all inhalers. Pulmonary function tests in 2023 and 2025 showed normalized

spirometry (FEV₁ >95%; FEV₁/FVC ≥83%). A pulmonologist concluded that the patient

no longer met diagnostic criteria for COPD. The patient has since resumed working andother physical activities, including running and long walks, without any recurrence of

respiratory symptoms. She currently reports full respiratory health.

This case represents an unusual example of long-term COPD remission, both in

symptoms and lung function, after stopping all standard medications. The improvement

occurred alongside daily use of low-dose singlet oxygen, suggesting a probable connection.

The recovery pattern supports further research into how this approach may reduce airway

inflammation and improve mucus clearance. Taken together, these observations support

further clinical investigation into SOT as an adjunctive treatment for COPD, particularly

in patients unresponsive to conventional therapies.

5.5.2.1. Healthcare Cost Implications of Asthma and COPD

In addition to its profound clinical burden, COPD imposes a substantial financial

toll. An analysis done in 2020170 estimated that respiratory diseases cost the U.S. healthcare

system $170.8 billion annually. Asthma accounted for the highest costs, followed by

COPD. For asthma, prescription drugs represented the largest share (48%), while for

COPD, hospitalizations (28.8%) and prescriptions (28.5%) were primary cost drivers.

Most COPD-related spending was concentrated in adults over 45, with nearly 70%

covered by public insurers. In contrast, asthma-related costs were more evenly distributed

across age groups.

These data highlight the potential value of adjunct therapies that can reduce

exacerbation rates, hospitalizations, and medication use. If low-dose SOT is validated in

future clinical studies, it may represent a cost-effective strategy that leverages endogenous

repair pathways rather than relying solely on pharmacological suppression.

5.5.3. Pneumonia

Pneumonia remains a significant global health concern, affecting over 500 million

individuals annually and accounting for approximately 4 million deaths, which is about 7%

of all global mortality. It is the leading infectious cause of death in children under five,

particularly in regions with limited access to medical care, such as South Asia and sub-

Saharan Africa.171

The condition arises when an infection, which can be bacterial, viral, or fungal,

triggers inflammation in the lungs, leading to alveolar fluid accumulation, impaired gas

exchange, and respiratory distress. Diagnosis and treatment are often complicated by

uncertainty around the causative pathogen and the rise in antimicrobial resistance, which

can hinder effective, targeted therapy.Observational Reports of SOT Use in Pneumonia

Several users of singlet oxygen therapy (SOT) have anecdotally reported significant

symptomatic relief within 1–3 days of starting therapy. These effects included:

• Improved breathing comfort

• Reduced coughing and phlegm production

• Relief of chest tightness or discomfort

• Increased physical energy and vitality

Some individuals also noted a shortened recovery timeline, which is typically protracted

in pneumonia, often lasting several weeks.

Proposed Mechanisms: The reported improvements in respiratory function and recovery

following singlet oxygen therapy may be explained by its capacity to modulate redox-

sensitive biological pathways. Low-dose oxidative stimulation is known to reduce local

inflammation, promote epithelial repair, and enhance mucociliary clearance, key

processes in the resolution of pneumonia. Additionally, by supporting immune regulation

and restoring redox balance in the lung microenvironment, singlet oxygen may facilitate

more efficient pathogen clearance and tissue recovery. These mechanisms, detailed in

Section 5, offer a biologically plausible framework for understanding how SOT could

accelerate symptom resolution and shorten recovery time in individuals with pneumonia.

5.5.4. Excess Phlegm and Mucociliary Function

Excessive phlegm production is a common and distressing symptom across a broad

spectrum of respiratory conditions, including asthma, 172 COPD,173 pneumonia,174 allergic

rhinitis,175 chronic exposure to tobacco smoke176 and other conditions177. While mucus is

essential for trapping pathogens and particulates,178 abnormal accumulation or viscosity

can impair airflow, reduce oxygenation, and heighten infection risk. In severe cases, it

contributes to hypoxemia, atelectasis, and respiratory failure.179

Conventional therapies, which include expectorants, mucolytics, bronchodilators,

and physical airway clearance techniques, often offer limited relief and may be impractical

or burdensome, especially in patients with reduced mobility or chronic illness. Moreover,

these treatments do not address upstream dysregulation in inflammatory or redox pathways

that often underlie mucus hypersecretion.Clinical Observations of Mucus Reduction Following SOT

Following SOT, users have consistently reported improvements in mucus-related

symptoms, including reductions in phlegm volume and viscosity. These reports span a

variety of respiratory conditions, including asthma, COPD, pneumonia, allergies, and

chronic smoking-related bronchitis. Notably, some individuals described the expulsion of

thick, dark mucus during early exposure, interpreted as a “detoxification phase,” followed

by an enduring sense of airway clearance and improved breathing.

Clinical Case: Discontinuation of Airway Suctioning in a Non-Communicative

Patient

non-communicative adult with a severe brain injury required routine nightly

suctioning to prevent aspiration due to excessive phlegm production. Following SOT, the

need for suctioning diminished and ultimately ceased. His mother and caregiver reported

improved sleep and overall well-being for both herself and the patient.

Proposed Mechanisms: These effects are consistent with redox-modulatory mechanisms

described in Section 5. Low-dose singlet oxygen likely reduces local airway inflammation,

downregulating the inflammatory pathways that drive excess mucus production.180 It may

also stimulate epithelial repair116 and enhance ciliary activity181, both of which are crucial

for effective mucociliary clearance. Additionally, redox-sensitive modulation of mucus

viscosity may lower its viscosity, facilitating easier expectoration.182

Taken together, these effects suggest that singlet oxygen may help restore the

mucus production-clearance cycle, particularly in individuals with impaired mucociliary

function or chronic inflammation. As a non-invasive, low-burden approach, this therapy

could complement existing treatments or offer relief to patients with refractory symptoms.

5.5.5. Biological Basis for Low-Level Singlet Oxygen Beneficial

Effect for Respiratory Diseases

The beneficial respiratory effects of low-dose singlet oxygen stem from its ability

to induce mild, transient oxidative stress, triggering a hormetic cellular response. This

controlled redox perturbation activates protective signaling pathways without

overwhelming endogenous antioxidant defenses.

Key mechanisms include the upregulation of antioxidant enzymes,183 such as

superoxide dismutase, catalase, and glutathione peroxidase, modulation of pro- and anti-

inflammatory mediators, and promotion of epithelial repair and regeneration.116 These

responses collectively restore redox balance, attenuate tissue inflammation,184 reducebronchoconstriction,185 and enhance mucociliary clearance,180,181 all of which are essential

for resolving respiratory infections and managing chronic airway disorders.

Additionally, singlet oxygen exposure has been proposed to stimulate autophagy

and mitochondrial biogenesis, contributing to enhanced metabolic resilience186 and

immune competence within pulmonary tissues. These redox- and autophagy-mediated

adaptations, as described in Sections 5 and 7, offer a plausible mechanistic foundation for

the observed improvements in respiratory function.

Taken together, these findings support low-dose singlet oxygen as a non-invasive

and physiologically adaptive modality for promoting respiratory health, particularly in

conditions characterized by chronic inflammation, redox imbalance, and epithelial

dysfunction.

5.6. COVID-19 and Related Pulmonary Inflammatory Conditions

The COVID-19 pandemic drew global attention to the devastating consequences of

dysregulated immune responses in viral pneumonia, where excessive cytokine release,

oxidative stress, and alveolar damage contribute to acute respiratory distress syndrome

(ARDS) and long-term pulmonary complications such as fibrosis and reduced oxygen

diffusion capacity.187 In the absence of curative antiviral therapies for severe cases, clinical

management has relied primarily on supportive interventions such as mechanical

ventilation and ECMO, both of which associated with high morbidity and long-term

impairment of lung function.188

5.6.1. Informal Reports of SOT During COVID-19

While no controlled clinical trials have yet assessed the efficacy of low-dose SOT

in COVID-19 management, a number of anecdotal reports describe apparent improvements

in respiratory function, oxygenation, and symptom resolution following its use. The

following case summaries are included for observational context:

Clinical Case 1: Rapid Symptom Resolution and Functional Recovery

A 15-year-old patient with confirmed COVID-19 presented with high fever

(~40 °C), significant labored breathing, and loss of taste and smell. Following the initiation

of SOT, the patient reported improved respiratory comfort, restoration of ambulation, and

return of olfactory and gustatory function.Clinical Case 2: Recovery from Severe Respiratory Distress

A 36-year-old recording artist experiencing severe respiratory symptoms during

acute COVID-19 infection, including significant pulmonary involvement and breathing

difficulties, reported progressive respiratory improvement and resumption of full

functional capacity after initiating SOT.

Clinical Case 3: Prevention of Hospitalization and Respiratory Recovery

A 39-year-old woman with acute deterioration following COVID-19 infection,

including loss of taste and smell, nausea, marked weakness, and episodes of respiratory

distress with declining oxygen saturation, requiring emergency medical attention. After

initiating SOT, she described phlegm expectoration and steady improvement in breathing

and energy, with eventual discontinuation of supplemental oxygen and symptom

resolution. Her family members, who also began SOT, reported similar improvement.

Proposed Mechanisms: These reports, while anecdotal and uncontrolled, align

mechanistically with the proposed redox-modulating and immunoregulatory effects of

low-dose singlet oxygen described in Sections 5 and 7. Their observational consistency

underscores the need for rigorous clinical trials to investigate its therapeutic potential in

acute viral respiratory illnesses.

5.7. Long COVID

Post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID, is

increasingly recognized as a multifactorial syndrome characterized by persistent symptoms

lasting weeks to months beyond the resolution of acute illness. According to the World

Health Organization, manifestations may include fatigue, dyspnea, cognitive dysfunction

(“brain fog”), autonomic instability, and multisystem involvement, often with delayed

onset. 189

Emerging evidence links these symptoms to chronic low-grade inflammation,

endothelial dysfunction, and mitochondrial dysregulation,190 aligning closely with the

redox imbalances and impaired energy metabolism described in Section 3. Long COVID

pathophysiology includes microvascular injury, immune dysregulation, and altered oxygen

delivery, which are all factors contributing to persistent oxidative stress and impaired

cellular bioenergetics.

Low-dose singlet oxygen exposure has been anecdotally associated with

improvements in these domains. Observational reports describe functional gains in

respiratory endurance, cognitive clarity, and fatigue reduction, suggesting that singlet

oxygen may support microcirculatory recovery, mitochondrial adaptation, and modulation

of chronic inflammation.Proposed Mechanisms: These outcomes are consistent with the hormetic mechanisms

discussed in Sections 5 and 7, particularly NRF2 activation, mitochondrial biogenesis, and

autophagy induction. Although formal validation is required, the absence of systemic

toxicity and the feasibility of continuous use make SOT a candidate for further research in

post-viral syndromes.

5.8. Anemia and Blood Disorders

Anemia is a condition in which there is a reduced number of red blood cells or

hemoglobin molecules, which are responsible for transporting oxygen throughout the body.

Consequently, reduced oxygen supply can impair tissue and organ function. In 2019,

around 25% of the global population was affected by anemia (over 1.5 billion people), with

the highest prevalence observed in children under five, reaching nearly 50%.191

One of the most common forms is anemia of chronic disease, also known as anemia

of inflammation.192 This type arises in the context of chronic illnesses such as autoimmune

disorders, cancer, or kidney failure, and is characterized by impaired erythropoiesis and

disturbed iron metabolism. The resulting anemia may further impair recovery by limiting

oxygen delivery to tissues and suppressing immune competence.

Anecdotal reports suggest that exposure to low-level singlet oxygen may support red

blood cell production, including in cases of longstanding or treatment-resistant anemia.

Clinical Case: Hematologic Improvement in a Patient with Refractory Anemia

A non-communicative adult patient with dementia, thyroid dysfunction, cardiac

disease, and severe anemia (hemoglobin <8 g/dL) had not responded to conventional

treatments for several years. After two months of SOT, hemoglobin levels increased to 10

g/dL and reached 10.2 g/dL after six months—levels not previously attained under standard

care. Additionally, improvements in thyroid and renal function were also reported.

Proposed Mechanisms: Mild oxidative stimulation may activate redox-sensitive

transcription factors, supporting hematopoiesis and counteracting inflammation-induced

suppression of red blood cell production.193 In particular, singlet oxygen may influence the

hypoxia-inducible factor (HIF) pathway, which regulates erythropoietin (EPO) production

in the bone marrow.194 Ferritin and iron metabolism may also be modulated through

oxidative signaling, contributing to more effective erythropoiesis.195,196 In parallel, the

mitigation of chronic inflammation via redox modulation may relieve inhibitory signals

that suppress bone marrow activity in anemia of inflammation.While these mechanisms are theoretically consistent with observed improvements,

further research is essential to determine whether low-dose singlet oxygen exposure has a

reproducible effect on hematologic parameters, and under which conditions it may be

clinically relevant.

5.9. Mitigating Cancer Treatment Side Effects and Enhanced Recovery

Chemotherapy remains one of the most commonly used and effective treatments

for various types of cancer, administered in an estimated 50–60% of cases during some

phase of treatment.197 While its efficacy is well established, chemotherapy is frequently

accompanied by debilitating side effects, including nausea, fatigue, alopecia, depression,

and anemia, which can jeopardize patient compliance and survival. Reducing the severity

of these adverse effects is essential to improving both treatment tolerance and outcomes.

Exposure to low levels of singlet oxygen has been anecdotally reported to reduce

toxicity and improve treatment tolerance in some individuals. The following clinical

observations are presented alongside plausible biological mechanisms, though they require

controlled validation.

Clinical Case 1: Cancer treatment side-effects: Myelosuppression, Nausea, Fatigue,

and Depression

A 50-year-old patient undergoing chemotherapy for lymphoma presented with

profound exhaustion, anemia (Hb 11.2 g/dL), breathlessness, and depression. Following

the initiation of SOT, the patient reportedly experienced a rapid improvement in energy

and his general mood. After one month, hemoglobin levels increased to 12.6 g/dL.

Subsequent rounds of chemotherapy were better tolerated, with notably reduced nausea

and fatigue.

Proposed Mechanisms: These effects may result from hormetic activation of protective

cellular pathways,including Nrf2-mediated antioxidant responses,48 mitochondrial

biogenesis,198 enhanced ATP production and improved redox homeostasis.199 Modulation

of inflammatory signaling,200 and improved mitochondrial function could account for the

observed improvements in fatigue and emotional resilience.

Clinical Case 2: Radiation-Induced Neuropathy and Sensory Disturbances

A patient with a history of extensive radiation therapy developed peripheral

neuropathy characterized by numbness and an atypical persistent “sharp smell,” consistent

with radiation-induced oxidative injury and microvascular compromise, which promote

neuronal apoptosis, demyelination, and fibrotic entrapment of nerves.201 After initiating

SOT, the patient reported a complete resolution of both sensory disturbances.Proposed Mechanisms: These outcomes may reflect activation of redox-sensitive

neuroprotective pathways, including restoration of mitochondrial redox balance, Nrf2-

regulated antioxidant responses, and modulation of glial-driven neuroinflammation (e.g.,

JNK and ERK signaling). These mechanisms are consistent with those previously

discussed in Sections 5 and 7.

5.10. Ocular Surface Health and Relief from Dry Eye Symptoms

Dry eye disease is a chronic disorder characterized by insufficient tear production

or excessive tear evaporation, resulting in ocular discomfort, surface inflammation, and

visual disturbances. Its pathophysiology often involves immune-mediated processes,

including macrophage activation and the release of pro-inflammatory cytokines such as

interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which amplify epithelial

damage and perpetuate symptoms.202

Conventional therapies, such as artificial tears, corticosteroids, and

immunosuppressants like cyclosporine—primarily aim to stabilize the tear film and

suppress inflammation. 203 More recently, antioxidant and redox-regulating strategies have

emerged as promising adjuncts, given growing evidence that oxidative stress is a key

contributor to dry eye pathology. 204

Anecdotal user reports suggest that exposure to low-level, non-irradiative singlet

oxygen may alleviate symptoms of both chronic dry eye and allergic periorbital irritation.

Users have described reduced ocular dryness and irritation, as well as rapid relief from

itching, redness, and swelling commonly associated with allergic conjunctivitis. These

improvements were sometimes observed within hours to days of initiating therapy.

Proposed Mechanisms: These effects may be mediated by the redox-sensitive and

immune-modulatory pathways discussed earlier in the review. Singlet oxygen, when

delivered at hormetic doses, likely induces mild oxidative preconditioning, which

downregulates inflammatory cascades and stabilizes epithelial function. Specifically,

suppression of mast cell degranulation and eosinophilic infiltration may reduce the release

of histamine, leukotrienes, IL-4, IL-5, and IL-13, thereby lowering vascular permeability

and sensory nerve activation.73 Additionally, SOT may restore epithelial barrier integrity

through Nrf2-driven antioxidant responses (Section 5.2), increasing resistance to allergens

and environmental irritants. These mechanisms may also contribute to broader immune

tolerance at the mucosal surface, as previously observed in respiratory and gastrointestinal

contexts (Section 7).Taken together, these observations support the possibility that singlet oxygen may

offer a non-pharmacological, mechanism-based intervention for both dry eye and allergic

periorbital conditions. Rather than masking symptoms, it may address underlying

biological dysfunction, illustrating a potential translational application of redox-hormetic

principles.

5.11. Future Research

In parallel to growing anecdotal observations presented above, academic research

into singlet oxygen as a therapeutic agent is also emerging. A 2024 doctoral dissertation

by Grimwood at the University of Derby205 laid the groundwork for a randomized, double-

blind controlled trial investigating the physiological and psychological effects of nightly

low-dose singlet oxygen exposure in individuals with COPD. While clinical results were

not yet reported at the time of submission, the study involved over 180 participants and

applied validated tools such as the CAT, ESS, and PSQI. Its rigorous patient-centered

design and emphasis on redox-modulating therapies underscore the increasing legitimacy

of this research direction and the need for peer-reviewed, controlled evaluations of clinical

outcomes.

6. Ruling Out the Placebo Effect: Evidence from Non-Conscious and

Indirect Exposure

One of the major challenges in evaluating novel therapeutic interventions,

particularly those involving subtle physiological modulation, is distinguishing true

biological effects from placebo responses. Placebo responses are mediated through central

nervous system circuits involving expectation, emotional modulation, and dopamine-

linked reward pathways.206 These mechanisms can produce transient symptom relief, but

do not activate cellular repair pathways, alter redox signaling, or regenerate damaged

tissue.207

In the case of singlet oxygen-enriched air, several cases presented in this review

provide strong evidence that the physiological benefits associated with low-dose singlet

oxygen are not merely psychological. These observations, particularly in individuals who

were unaware of the intervention or incapable of expectancy-based responses, provide

strong evidence for a biological, rather than psychological, basis for the effects.

As previously described in the section on mucociliary function, a severely brain-

injured young man, fully bedridden and non-communicative, experienced a sustained and

documented reduction in the need for routine suctioning following the introduction of the

singlet oxygen-enriched air generator. The cessation of routine suctioning, previously

required nightly to prevent choking, occurred without any awareness or behavioral changeon the part of the patient, offering compelling support for a direct physiological effect of

the therapy on mucociliary function.

A similar conclusion can be drawn from the case reported under anemia and blood

disorders, where an elderly man with dementia and chronic illness exhibited a sustained

rise in hemoglobin levels after exposure to singlet oxygen-enriched air. Given his cognitive

impairment and lack of knowledge regarding the intervention, the improvement in anemia,

thyroid, and renal parameters could not have been driven by expectancy effects.

In the context of oncological support, the case of a terminal lymphoma patient,

documented under supporting cancer treatment and recovery, showed an unexpectedly

rapid return of verbal communication, appetite, and increased energy shortly after the

initiation of low-level ambient singlet oxygen generator use. Although this patient may

have been marginally aware of environmental changes, the timing, magnitude, and

multifaceted nature of the improvements, including enhanced chemotherapy tolerance and

rising hemoglobin levels, suggest physiological mechanisms were at play.

Further support comes from multiple reports involving young children and infants,

discussed under respiratory conditions and excess phlegm, who experienced improvements

in breathing, mucus clearance, and sleep quality. Given their developmental stage and

limited awareness, placebo responses are not a plausible explanation in these cases.

These observations, taken together across multiple populations and physiological

systems, indicate that the benefits of singlet oxygen exposure are not the result of

suggestion or expectation. Instead, they reflect a pattern of redox-modulated physiological

responses consistent with hormetic activation of repair and defense pathways.

7. Singlet Oxygen: A Pathway to Regulated Preventive Therapy

Low-dose exposure to singlet oxygen represents a fundamentally different

therapeutic strategy compared to conventional pharmaceuticals. While most drugs act by

targeting specific receptors or pathways, singlet oxygen functions mainly through

hormesis, which is a mild oxidative stimulus that activates broad, evolutionarily conserved

defense systems. These include autophagy, upregulation of antioxidant enzymes, and

metabolic adaptation. 105

Such pathways are self-limiting, highly regulated, and sensitive to context. This

enables singlet oxygen to maintain physiological balance without the risks of chronic

overstimulation or suppression often associated with pharmacological agents.208 These

characteristics make it especially relevant to preventive medicine, where early modulation

of redox signaling can reduce inflammation, enhance cellular resilience, and delay disease

progression. 123Moreover, unlike many drug-based interventions, the protective responses

triggered by singlet oxygen are not heavily influenced by individual genetic

polymorphisms or metabolic profiles. This broad compatibility increases its potential

applicability across diverse populations.Error! Bookmark not defined. Together, these features p

osition singlet oxygen as a novel, non-pharmacological tool for modulating redox-sensitive

biological networks to prevent disease onset and maintain long-term physiological

equilibrium.

8. Conclusions

This review highlights the emerging role of singlet oxygen as a hormetic agent

capable of inducing protective and adaptive cellular responses when delivered at low

concentrations. Historically regarded primarily as a cytotoxic species, singlet oxygen is

now recognized for its ability to modulate key signaling pathways that regulate antioxidant

defenses, autophagy, and inflammation.

By activating regulatory circuits such as the Nrf2-Keap1 axis, MAPK signaling,

and JNK-mediated autophagy, mild oxidative stress initiated by singlet oxygen promotes

detoxification, cellular repair, and long-term resilience to environmental and physiological

challenges.

These mechanistic insights are supported by case observations presented in this

review, which document improvements in a wide array of conditions, including asthma,

COPD, sleep disturbances, anemia, and chemotherapy-related fatigue, following exposure

to singlet oxygen-enriched air. The singlet oxygen-enriched air generator, which enables

safe and non-invasive delivery of singlet oxygen under ambient conditions, represents a

promising tool for translating these physiological mechanisms into therapeutic and

preventive applications.

Together, the evidence supports the view that low-dose singlet oxygen can serve as

a valuable adjunct in regenerative, anti-inflammatory, and resilience-enhancing

interventions—laying the groundwork for future clinical validation and wider integration

into health-supportive strategies.9. References

1 (a) Klotz, L. O., Kröncke, K. D., & Sies, H. (2003). Singlet oxygen-induced signaling effects in mammalian

cells. Photochemical & photobiological sciences, 2(2), 88-94. (b) Jones, D. P., & Sies, H. (2015). The redox

code. Antioxidants & redox signaling, 23(9), 734-746.

2 Zheng, C., Chen, J. P., Wang, X. W., & Li, P. (2025). Reactive Oxygen Species in Plants: Metabolism,

Signaling, and Oxidative Modifications. Antioxidants, 14(6), 617.

3 Murotomi, K., Umeno, A., Shichiri, M., Tanito, M., & Yoshida, Y. (2023). Significance of singlet oxygen

molecule in pathologies. International Journal of Molecular Sciences, 24(3), 2739.

4 Calabrese, E. J., & Mattson, M. P. (2011). Hormesis provides a generalized quantitative estimate of

biological plasticity. Journal of cell communication and signaling, 5(1), 25-38.

5 Wilkinson, F., Helman, W. P., & Ross, A. B. (1995). Rate constants for the decay and reactions of the

lowest electronically excited singlet state of molecular oxygen in solution. An expanded and revised

compilation. Journal of Physical and Chemical Reference Data, 24(2), 663-677.

6 (a) Hasegawa, K., Yamada, K., Sasase, R., Miyazaki, R., Kikuchi, A., & Yagi, M. (2008). Direct

measurements of absolute concentration and lifetime of singlet oxygen in the gas phase by electron

paramagnetic resonance. Chemical Physics Letters, 457(4-6), 312-314. (b) Wang, K. K., Song, S., Jung, S.

J., Hwang, J. W., Kim, M. G., Kim, J. H., … & Kim, Y. R. (2020). Lifetime and diffusion distance of singlet

oxygen in air under everyday atmospheric conditions. Physical Chemistry Chemical Physics, 22(38), 21664-

21671.

7 Hurst, J. R., McDonald, J. D., & Schuster, G. B. (1982). Lifetime of singlet oxygen in solution directly

determined by laser spectroscopy. Journal of the American Chemical Society, 104(7), 2065-2067.

8 (a) Noronha-Dutra, A. A., Epperlein, M. M., & Woolf, N. (1993). Reaction of nitric oxide with hydrogen

peroxide to produce potentially cytotoxic singlet oxygen as a model for nitric oxide-mediated killing. FEBS

letters, 321(1), 59-62. (b) Kanofsky, J. R. (1984). Singlet oxygen production by chloroperoxidase-hydrogen

peroxide-halide systems. Journal of Biological Chemistry, 259(9), 5596-5600. (c) Foote, C. S., Wexler, S.,

Ando, W., & Higgins, R. (1968). Chemistry of singlet oxygen. IV. Oxygenations with hypochlorite-hydrogen

peroxide. Journal of the American Chemical Society, 90(4), 975-981. (d) Stephenson, L. M., & McClure, D.

E. (1973). Mechanisms in phosphite ozonide decomposition to phosphate esters and singlet oxygen. Journal

of the American Chemical Society, 95(9), 3074-3076.

9 Barry Halliwell; John MC. (1982) Free Radical in Biology and Medicine. Second Edition. Clarwndon Press.

OxFord.

10 Makuch, S., Dróżdż, M., Makarec, A., Ziółkowski, P., & Woźniak, M. (2022). An Update on

Photodynamic Therapy of Psoriasis—Current Strategies and Nanotechnology as a Future

Perspective. International journal of molecular sciences, 23(17), 9845.

11 Jiang, J., Lv, X., Cheng, H., Yang, D., Xu, W., Hu, Y., … & Zeng, G. (2024). Type I photodynamic

antimicrobial therapy: principles, progress, and future perspectives. Acta Biomaterialia, 177, 1-19.

12 Singh, S., & Awasthi, R. (2023). Breakthroughs and bottlenecks of psoriasis therapy: Emerging trends and

advances in lipid based nano-drug delivery platforms for dermal and transdermal drug delivery. Journal of

Drug Delivery Science and Technology, 104548.

13 DeRosa, M. C., & Crutchley, R. J. (2002). Photosensitized singlet oxygen and its

applications. Coordination Chemistry Reviews, 233, 351-371.

14 (a) Eisenberg, W. C., & DeSilva, M. (1990). Atmospheric gas phase generation of singlet oxygen by

homogeneous photosensitization. Tetrahedron letters, 31(41), 5857-5860. (b) Eisenberg, W. C., & DeSilva,

M. (1990). Atmospheric gas phase generation of singlet oxygen by homogeneous photosensitization.

Tetrahedron letters, 31(41), 5857-5860. (c) Funken, K. H., Horneck, G., Milow, B., Schafer, M., Schmitz,

C., Faust, D., … & Sattlegger, M. (2000). U.S. Patent No. 6,107,480. Washington, DC: U.S. Patent and

Trademark Office. (d) Sunday, M. O., & Sakugawa, H. (2020). A simple, inexpensive method for gas-phase

singlet oxygen generation from sensitizer-impregnated filters: Potential application to bacteria/virus

inactivation and pollutant degradation. Science of the Total Environment, 746, 141186.

15 (a) Gorbanev, Y., & Bogaerts, A. (2018). Chemical detection of short-lived species induced in aqueous

media by atmospheric pressure plasma. In Atmospheric Pressure Plasma-from Diagnostics to Applications.

IntechOpen. (b) Cabrellon, G., Tampieri, F., Rossa, A., Barbon, A., Marotta, E., & Paradisi, C. (2020).

Application of fluorescence-based probes for the determination of superoxide in water treated with air non-thermal plasma. ACS sensors, 5(9), 2866-2875. (c) Aggelopoulos, C. A., Tataraki, D., & Rassias, G. (2018).

Degradation of atrazine in soil by dielectric barrier discharge plasma–potential singlet oxygen mediation.

Chemical Engineering Journal, 347, 682-694. (d) Jablonowski, H., Santos Sousa, J., Weltmann, K. D.,

Wende, K., & Reuter, S. (2018). Quantification of the ozone and singlet delta oxygen produced in gas and

liquid phases by a non-thermal atmospheric plasma with relevance for medical treatment. Scientific reports,

8(1), 12195. (e) Lim, J., Park, S., Ryu, S., Park, S., & Kim, M. S. (2025). Different inactivation mechanisms

of Staphylococcus aureus and Escherichia coli in water by reactive oxygen and nitrogen species generated

from an argon plasma jet. Environmental Science & Technology, 59(6), 3276-3285.

16 Braginskiy, O. V., Vasilieva, A. N., Klopovskiy, K. S., Kovalev, A. S., Lopaev, D. V., Proshina, O. V., …

& Rakhimov, A. T. (2005). Singlet oxygen generation in O2 flow excited by RF discharge: I. Homogeneous

discharge mode: α-mode. Journal of Physics D: Applied Physics, 38(19), 3609.

17 (a) Kuk, S. K., Ji, S. M., Kang, S., Yang, D. S., Kwon, H. J., Koo, M. S., … & Lee, H. C. (2023). Singlet-

oxygen-driven photocatalytic degradation of gaseous formaldehyde and its mechanistic study. Applied

Catalysis B: Environmental, 328, 122463. (b) Zollo, A., Livraghi, S., Giamello, E., Cioni, A., Dami, V.,

Lorenzi, G., … & Zaleska-Medynska, A. (2023). How to guide photocatalytic applications of titanium dioxide

co-doped with nitrogen and carbon by modulating the production of reactive oxygen species. Journal of

Environmental Chemical Engineering, 11(6), 111523. (c) Li, Q., Zhao, J., Shang, H., Ma, Z., Cao, H., Zhou,

Y., … & Li, H. (2022). Singlet Oxygen and Mobile Hydroxyl Radicals Co-operating on Gas–solid Catalytic

Reaction Interfaces for Deeply Oxidizing NO x. Environmental Science & Technology, 56(9), 5830-5839.

(d) Ibhadon, A. O., & Fitzpatrick, P. (2013). Heterogeneous photocatalysis: recent advances and applications.

Catalysts, 3(1), 189-218. (e) Shi, Y., Yang, Z., Shi, L., Li, H., Liu, X., Zhang, X., … & Zhang, L. (2022).

Surface boronizing can weaken the excitonic effects of BiOBr nanosheets for efficient O2 activation and

selective NO oxidation under visible light irradiation. Environmental Science & Technology, 56(20), 14478-

14486. (f) Yaghmaei Sabegh, M. (2024). Advancements in Photochemistry and Flow Systems for Synthesis

and Analysis (Doctoral dissertation, Université d’Ottawa| University of Ottawa).

18 Badash, Z. (2021). U.S. Patent No. 11,007,129. Washington, DC: U.S. Patent and Trademark Office.

19 Carbogno, C., Groß, A., Meyer, J., & Reuter, K. (2013). O2 Adsorption Dynamics at Metal Surfaces: Non-

Adiabatic Effects, Dissociation and Dissipation. In Dynamics of Gas-Surface Interactions (pp. 389-419).

Springer Berlin Heidelberg.

20 (1) Ihalagedara, H. B., Xu, Q., Greer, A., & Lyons, A. M. (2025). Singlet oxygen generation on a

superhydrophobic surface: Effect of photosensitizer coating and incident wavelength on 1O2 yields.

Photochemistry and Photobiology, 101(1), 167-179. (2) Arpa, E. M., & Corral, I. (2023). Unveiling

Photodegradation and Photosensitization Mechanisms of Unconjugated Pterins. Chemistry–A European

Journal, 29(29), e202300519.

21 Devasagayam, T., & Kamat, J. P. (2002). Biological significance of singlet oxygen.

22 Dmitrieva, V. A., Tyutereva, E. V., & Voitsekhovskaja, O. V. (2020). Singlet oxygen in plants: Generation,

detection, and signaling roles. International journal of molecular sciences, 21(9), 3237.

23 Kiryu, C., Makiuchi, M., Miyazaki, J., Fujinaga, T., & Kakinuma, K. (1999). mu-H2O2-chloride system.

FEBS letters, 443(2), 154-158.

24 Sun, Y., Lu, Y., Saredy, J., Wang, X., Drummer IV, C., Shao, Y., … & Yang, X. (2020). ROS systems are

a new integrated network for sensing homeostasis and alarming stresses in organelle metabolic

processes. Redox biology, 37, 101696.

25 Murphy, M. P. (2009). How mitochondria produce reactive oxygen species. Biochemical journal, 417(1),

1-13.

26 Szechyńska-Hebda, M., Ghalami, R. Z., Kamran, M., Van Breusegem, F., & Karpiński, S. (2022). To Be

or Not to Be? Are Reactive Oxygen Species, Antioxidants, and Stress Signalling Universal Determinants of

Life or Death? Cells, 11(24), 4105.

27 Davies, M. J. (2004). Reactive species formed on proteins exposed to singlet oxygen. Photochemical &

Photobiological Sciences, 3, 17-25.

28 (a) Di Mascio, P., Martinez, G. R., Miyamoto, S., Ronsein, G. E., Medeiros, M. H., & Cadet, J. (2019).

Singlet molecular oxygen reactions with nucleic acids, lipids, and proteins. Chemical reviews, 119(3), 2043-

2086. (b) Juan, C. A., Pérez de la Lastra, J. M., Plou, F. J., & Pérez-Lebeña, E. (2021). The chemistry of

reactive oxygen species (ROS) revisited: outlining their role in biological macromolecules (DNA, lipids and

proteins) and induced pathologies. International Journal of Molecular Sciences, 22(9), 4642.

29 (a) Forman, H. J., & Zhang, H. (2021). Targeting oxidative stress in disease: promise and limitations of

antioxidant therapy. Nature Reviews Drug Discovery, 20(9), 689-709. (b) Brieger, K., Schiavone, S., MillerJr, F. J., & Krause, K. H. (2012). Reactive oxygen species: from health to disease. Swiss medical weekly,

142, w13659. (c) Rahman, T., Hosen, I., Islam, M. T., & Shekhar, H. U. (2012). Oxidative stress and human

health. Advances in Bioscience and Biotechnology, 3(07), 997.

30 Sokolovski, S. G., Rafailov, E. U., Abramov, A. Y., & Angelova, P. R. (2021). Singlet oxygen stimulates

mitochondrial bioenergetics in brain cells. Free Radical Biology and Medicine, 163, 306-313.

31 Dmitrieva, V. A., Tyutereva, E. V., & Voitsekhovskaja, O. V. (2020). Singlet Oxygen in Plants:

Generation, Detection, and Signaling Roles. International journal of molecular sciences, 21(9), 3237.

32 Saed-Moucheshi, A., Sohrabi, F., & Shirkhani, A. (2023). A review on reactive oxygen species (ROS):

production, function, and their influence on plants. Crop Biotechnology, 13(44), 53-70.

33 Ziegelhoffer, E. C., & Donohue, T. J. (2009). Bacterial responses to photo-oxidative stress. Nature Reviews

Microbiology, 7(12), 856-863.

34 (a) Maharjan, P. S., & Bhattarai, H. K. (2022). Singlet oxygen, photodynamic therapy, and mechanisms of

cancer cell death. Journal of oncology, 2022(1), 7211485. (b) Akazawa-Ogawa, Y., Shichiri, M., Nishio, K.,

Yoshida, Y., Niki, E., & Hagihara, Y. (2015). Singlet-oxygen-derived products from linoleate activate Nrf2

signaling in skin cells. Free Radical Biology and Medicine, 79, 164-175.

35 Poli, G., Leonarduzzi, G., Biasi, F., & Chiarpotto, E. (2004). Oxidative stress and cell signalling. Current

medicinal chemistry, 11(9), 1163-1182.

36 (a) Iuliano, L. (2011). Pathways of cholesterol oxidation via non-enzymatic mechanisms. Chemistry and

physics of lipids, 164(6), 457-468. (b) Kulig, W., Olżyńska, A., Jurkiewicz, P., Kantola, A. M., Komulainen,

S., Manna, M., … & Jungwirth, P. (2015). Cholesterol under oxidative stress—How lipid membranes sense

oxidation as cholesterol is being replaced by oxysterols. Free radical biology and medicine, 84, 30-41.

37 (a) Lorenzen, I., Eble, J. A., & Hanschmann, E. M. (2021). Thiol switches in membrane proteins-

Extracellular redox regulation in cell biology. Biological chemistry, 402(3), 253-269. (b) Bigelow, D. J., &

Squier, T. C. (2011). Thioredoxin-dependent redox regulation of cellular signaling and stress response

through reversible oxidation of methionines. Molecular Biosystems, 7(7), 2101-2109.

38 Gems, D., & Partridge, L. (2008). Stress-response hormesis and aging:“that which does not kill us makes

us stronger”. Cell metabolism, 7(3), 200-203.

39 Chirumbolo, S., & Bjørklund, G. (2017). PERM hypothesis: the fundamental machinery able to elucidate

the role of xenobiotics and hormesis in cell survival and homeostasis. International Journal of Molecular

Sciences, 18(1), 165.

40 Dattilo, S., Mancuso, C., Koverech, G., Di Mauro, P., Ontario, M. L., Petralia, C. C., … & Calabrese, V.

(2015). Heat shock proteins and hormesis in the diagnosis and treatment of neurodegenerative diseases.

Immunity & Ageing, 12(1), 20.

41 Pinches, I. J. L., Pinches, Y. L., Johnson, J. O., Haddad, N. C., Boueri, M. G., Oke, L. M., & Haddad, G.

E. (2022). Could “cellular exercise” be the missing ingredient in a healthy life? Diets, caloric restriction, and

exercise-induced hormesis. Nutrition, 99, 111629.

42 Burtscher, J., & Samaja, M. (2024). Healthy aging at moderate altitudes: hypoxia and hormesis.

Gerontology, 70(11), 1152-1160.

43 Ristow, M., & Schmeisser, K. (2014). Mitohormesis: promoting health and lifespan by increased levels of

reactive oxygen species (ROS). Dose-response, 12(2), dose-response.

44 (a) Kasai, S., Shimizu, S., Tatara, Y., Mimura, J., & Itoh, K. (2020). Regulation of Nrf2 by mitochondrial

reactive oxygen species in physiology and pathology. Biomolecules, 10(2), 320.(b) Shokeir, A. A., Hussein,

A. M., Barakat, N., Abdelaziz, A., Elgarba, M., & Awadalla, A. (2014). Activation of nuclear factor erythroid

2‐related factor 2 (N rf2) and N rf‐2‐dependent genes by ischaemic pre‐conditioning and post‐conditioning:

new adaptive endogenous protective responses against renal ischaemia/reperfusion injury. Acta Physiologica,

210(2), 342-353.

45 Jomova, K., Alomar, S. Y., Alwasel, S. H., Nepovimova, E., Kuca, K., & Valko, M. (2024). Several lines

of antioxidant defense against oxidative stress: antioxidant enzymes, nanomaterials with multiple enzyme-

mimicking activities, and low-molecular-weight antioxidants. Archives of toxicology, 98(5), 1323-1367.

46 Shaw, P., & Chattopadhyay, A. (2020). Nrf2–ARE signaling in cellular protection: Mechanism of action

and the regulatory mechanisms. Journal of Cellular Physiology, 235(4), 3119-3130.

47 Lu, S. C. (2013). Glutathione synthesis. Biochimica et Biophysica Acta (BBA)-General Subjects, 1830(5),

3143-3153.

48 Kensler, T. W., Wakabayashi, N., & Biswal, S. (2007). Cell survival responses to environmental stresses

via the Keap1-Nrf2-ARE pathway. Annu. Rev. Pharmacol. Toxicol., 47(1), 89-116.49 Conrad, M., & Pratt, D. A. (2019). The chemical basis of ferroptosis. Nature chemical biology, 15(12),

1137-1147.

50 Flohé, L., Toppo, S., & Orian, L. (2022). The glutathione peroxidase family: Discoveries and mechanism.

Free Radical Biology and Medicine, 187, 113-122.

51 Ma, Q. (2013). Role of nrf2 in oxidative stress and toxicity. Annual review of pharmacology and

toxicology, 53(1), 401-426.

52 Grek, C. L., Zhang, J., Manevich, Y., Townsend, D. M., & Tew, K. D. (2013). Causes and consequences

of cysteine S-glutathionylation. Journal of Biological Chemistry, 288(37), 26497-26504.

53 Telorack, M., Meyer, M., Ingold, I., Conrad, M., Bloch, W., & Werner, S. (2016). A glutathione-Nrf2-

thioredoxin cross-talk ensures keratinocyte survival and efficient wound repair. PLoS genetics, 12(1),

e1005800.

54 (a) Ross, D., & Siegel, D. (2021). The diverse functionality of NQO1 and its roles in redox control. Redox

Biology, 41, 101950. (b) Lee, W. S., Ham, W., & Kim, J. (2021). Roles of NAD (P) H: quinone

oxidoreductase 1 in diverse diseases. Life, 11(12), 1301.

55 (a) Waza, A. A., Hamid, Z., Ali, S., Bhat, S. A., & Bhat, M. A. (2018). A review on heme oxygenase-1

induction: is it a necessary evil. Inflammation Research, 67, 579-588. (b) Loboda, A., Damulewicz, M., Pyza,

E., Jozkowicz, A., & Dulak, J. (2016). Role of Nrf2/HO-1 system in development, oxidative stress response

and diseases: an evolutionarily conserved mechanism. Cellular and molecular life sciences, 73, 3221-3247.

(c) Son, Y., Lee, J. H., Chung, H. T., & Pae, H. O. (2013). Therapeutic roles of heme oxygenase‐1 in

metabolic diseases: curcumin and resveratrol analogues as possible inducers of heme oxygenase‐1. Oxidative

medicine and cellular longevity, 2013(1), 639541.

56 Knoops, B., Argyropoulou, V., Becker, S., Ferté, L., & Kuznetsova, O. (2016). Multiple roles of

peroxiredoxins in inflammation. Molecules and cells, 39(1), 60-64.

57 Lu, J., & Holmgren, A. (2014). The thioredoxin antioxidant system. Free radical biology and medicine,

66, 75-87.

58 Hao, X., Zhao, B., Towers, M., Liao, L., Monteiro, E. L., Xu, X., … & Zhang, R. (2024). TXNRD1 drives

the innate immune response in senescent cells with implications for age-associated inflammation. Nature

Aging, 4(2), 185-197.

59 Bafana, A., Dutt, S., Kumar, A., Kumar, S., & Ahuja, P. S. (2011). The basic and applied aspects of

superoxide dismutase. Journal of Molecular Catalysis B: Enzymatic, 68(2), 129-138.

60 Kirkman, H. N., & Gaetani, G. F. (2007). Mammalian catalase: a venerable enzyme with new mysteries.

Trends in biochemical sciences, 32(1), 44-50.

61 Greeshma, M. V., Baidya, A., Mabalirajan, U., Madhunapantula, S. V., Thimmulappa, R. K., & Mahesh,

P. A. (2024). Deciphering the role of 12/15-lipoxygenase in asthma: insights into mitochondrial dysfunction

and therapeutic implications. Exploration of Asthma & Allergy, 2(6), 529-550.

62 Zhang, J., Zhang, M., Tatar, M., & Gong, R. (2025). Keap1-independent Nrf2 regulation: A novel

therapeutic target for treating kidney disease. Redox Biology, 103593.

63 Dong, H., Lyu, Y., Huang, C. Y., & Tsai, S. Y. (2025). Limiting cap-dependent translation increases 20S

proteasomal degradation and protects the proteomic integrity in autophagy-deficient skeletal muscle.

Autophagy, 21(6), 1212-1227.

64 Kiang, J. G., & Tsokos, G. C. (1998). Heat shock protein 70 kDa: molecular biology, biochemistry, and

physiology. Pharmacology & therapeutics, 80(2), 183-201.

65 Ameri, K., & Harris, A. L. (2008). Activating transcription factor 4. The international journal of

biochemistry & cell biology, 40(1), 14-21.

66 (a) Richter-Landsberg, C., Wyttenbach, A., & Arrigo, A. P. (2009). The role of heat shock proteins during

neurodegeneration in Alzheimer’s, Parkinson’s and Huntington’s disease. Heat shock proteins in neural cells,

81-99. (b) Zhang, N., Nao, J., Zhang, S., & Dong, X. (2024). Novel insights into the activating transcription

factor 4 in Alzheimer’s disease and associated aging-related diseases: Mechanisms and therapeutic

implications. Frontiers in Neuroendocrinology, 101144.

67 (a) Bjørklund, G., Zou, L., Peana, M., Chasapis, C. T., Hangan, T., Lu, J., & Maes, M. (2022). The role of

the thioredoxin system in brain diseases. Antioxidants, 11(11), 2161. (b) Cimini, A., Gentile, R., Angelucci,

F., Benedetti, E., Pitari, G., Giordano, A., & Ippoliti, R. (2013). Neuroprotective effects of PrxI over‐

expression in an in vitro human Alzheimer’s disease model. Journal of cellular biochemistry, 114(3), 708-

715. (c) Zeng, X. S., Jia, J. J., Kwon, Y., Wang, S. D., & Bai, J. (2014). The role of thioredoxin-1 insuppression of endoplasmic reticulum stress in Parkinson disease. Free Radical Biology and Medicine, 67,

10-18.

68 (a) Ahsan, M. K., Lekli, I., Ray, D., Yodoi, J., & Das, D. K. (2009). Redox regulation of cell survival by

the thioredoxin superfamily: an implication of redox gene therapy in the heart. Antioxidants & redox

signaling, 11(11), 2741-2758. (b) Chong, C. R., Chan, W. P. A., Nguyen, T. H., Liu, S., Procter, N. E., Ngo,

D. T., … & Horowitz, J. D. (2014). Thioredoxin-interacting protein: pathophysiology and emerging

pharmacotherapeutics in cardiovascular disease and diabetes. Cardiovascular drugs and therapy, 28, 347-

360.

69 Yang, Z. F., Drumea, K., Mott, S., Wang, J., & Rosmarin, A. G. (2014). GABP transcription factor (nuclear

respiratory factor 2) is required for mitochondrial biogenesis. Molecular and cellular biology, 34(17), 3194-

3201.

70 (a) Gureev, A. P., Shaforostova, E. A., & Popov, V. N. (2019). Regulation of mitochondrial biogenesis as

a way for active longevity: interaction between the Nrf2 and PGC-1α signaling pathways. Frontiers in

genetics, 10, 435. (b) St-Pierre, J., Drori, S., Uldry, M., Silvaggi, J. M., Rhee, J., Jäger, S., … & Spiegelman,

B. M. (2006). Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional

coactivators. Cell, 127(2), 397-408.

71 (a) Maiorino, M., Conrad, M., & Ursini, F. (2018). GPx4, lipid peroxidation, and cell death: discoveries,

rediscoveries, and open issues. Antioxidants & redox signaling, 29(1), 61-74. (b) Lu, L., Oveson, B. C., Jo,

Y. J., Lauer, T. W., Usui, S., Komeima, K., … & Campochiaro, P. A. (2009). Increased expression of

glutathione peroxidase 4 strongly protects retina from oxidative damage. Antioxidants & redox signaling,

11(4), 715-724.

72 Clements, C. M., McNally, R. S., Conti, B. J., Mak, T. W., & Ting, J. P. Y. (2006). DJ-1, a cancer-and

Parkinson’s disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2.

Proceedings of the National Academy of Sciences, 103(41), 15091-15096.

73 Kobayashi, E. H., Suzuki, T., Funayama, R., Nagashima, T., Hayashi, M., Sekine, H., … & Yamamoto, M.

(2016). Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine

transcription. Nature communications, 7(1), 1-14.

74 Xu, W. D., Yang, C., & Huang, A. F. (2024). The role of Nrf2 in immune cells and inflammatory

autoimmune diseases: a comprehensive review. Expert Opinion on Therapeutic Targets, 28(9), 789-806.

75 (a) Dodson, M., Shakya, A., Anandhan, A., Chen, J., Garcia, J. G., & Zhang, D. D. (2022). NRF2 and

diabetes: the good, the bad, and the complex. Diabetes, 71(12), 2463-2476. (b) Vasileva, L. V., Savova, M.

S., Amirova, K. M., Dinkova-Kostova, A. T., & Georgiev, M. I. (2020). Obesity and NRF2-mediated

cytoprotection: Where is the missing link?. Pharmacological research, 156, 104760. (c) Li, S., Eguchi, N.,

Lau, H., & Ichii, H. (2020). The role of the Nrf2 signaling in obesity and insulin resistance. International

journal of molecular sciences, 21(18), 6973.

76 (a) Zhang, Y., Wang, J., Wang, Y., & Lei, K. (2024). Nrf2/HO-1 signaling activation alleviates cigarette

smoke-induced inflammation in chronic obstructive pulmonary disease by suppressing NLRP3-mediated

pyroptosis. Journal of Cardiothoracic Surgery, 19(1), 58. (b) Audousset, C., McGovern, T., & Martin, J. G.

(2021). Role of Nrf2 in disease: novel molecular mechanisms and therapeutic approaches–pulmonary

disease/asthma. Frontiers in Physiology, 12, 727806.

77 Saha, S., Buttari, B., Profumo, E., Tucci, P., & Saso, L. (2022). A perspective on Nrf2 signaling pathway

for neuroinflammation: a potential therapeutic target in Alzheimer’s and Parkinson’s diseases. Frontiers in

cellular neuroscience, 15, 787258.

78 Shi, T., & Dansen, T. B. (2020). Reactive oxygen species induced p53 activation: DNA damage, redox

signaling, or both?. Antioxidants & Redox Signaling, 33(12), 839-859.

79 Klotz, L. O., Briviba, K., & Sies, H. (1997). Singlet oxygen mediates the activation of JNK by UVA

radiation in human skin fibroblasts. FEBS letters, 408(3), 289-291.

80 Klionsky, D. J. (2005). The molecular machinery of autophagy: unanswered questions. Journal of cell

science, 118(Pt 1), 7.

81 (a) Wei, Y., Pattingre, S., Sinha, S., Bassik, M., & Levine, B. (2008). JNK1-mediated phosphorylation of

Bcl-2 regulates starvation-induced autophagy. Molecular cell, 30(6), 678-688. (b) Yu, C., Minemoto, Y.,

Zhang, J., Liu, J., Tang, F., Bui, T. N., … & Lin, A. (2004). JNK suppresses apoptosis via phosphorylation

of the proapoptotic Bcl-2 family protein BAD. Molecular cell, 13(3), 329-340.

82 (a) Zhou, J., Li, X. Y., Liu, Y. J., Feng, J., Wu, Y., Shen, H. M., & Lu, G. D. (2022). Full-coverage

regulations of autophagy by ROS: from induction to maturation. Autophagy, 18(6), 1240-1255. (b) Przygoda,

M., Bartusik-Aebisher, D., Dynarowicz, K., Cieślar, G., Kawczyk-Krupka, A., & Aebisher, D. (2023).Cellular mechanisms of singlet oxygen in photodynamic therapy. International Journal of Molecular

Sciences, 24(23), 16890. (c) Liang, P., Kolodieznyi, D., Creeger, Y., Ballou, B., & Bruchez, M. P. (2020).

Subcellular singlet oxygen and cell death: location matters. Frontiers in chemistry, 8, 592941.

83 (a) Davies, K. J. (2000). Oxidative stress, antioxidant defenses, and damage removal, repair, and

replacement systems. IUBMB life, 50(4‐5), 279-289. (b) Gao, Q. (2019). Oxidative stress and autophagy.

Autophagy: biology and diseases: basic science, 179-198.

84 (a) Kaminskyy, V. O., & Zhivotovsky, B. (2014). Free radicals in cross talk between autophagy and

apoptosis. Antioxidants & redox signaling, 21(1), 86-102. (b) Yue, J., & López, J. M. (2020). Understanding

MAPK signaling pathways in apoptosis. International journal of molecular sciences, 21(7), 2346.

85 Kang, R., Zeh, H. J., Lotze, M. T., & Tang, D. J. C. D. (2011). The Beclin 1 network regulates autophagy

and apoptosis. Cell Death & Differentiation, 18(4), 571-580.

86 Asgari, R., Yarani, R., Mohammadi, P., & Emami Aleagha, M. S. (2022). HIF-1α in the crosstalk between

reactive oxygen species and autophagy process: a review in multiple sclerosis. Cellular and molecular

neurobiology, 42(7), 2121-2129.

87 Romero, N. R., & Agostinis, P. (2014). Molecular mechanisms underlying the activation of autophagy

pathways by reactive oxygen species and their relevance in cancer progression and therapy. In Autophagy:

Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging (pp. 159-178). Academic Press.

88 Horan, M. P., Pichaud, N., & Ballard, J. W. O. (2012). Quantifying mitochondrial dysfunction in complex

diseases of aging. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 67(10),

1022-1035.

89 Osellame, L. D., Rahim, A. A., Hargreaves, I. P., Gegg, M. E., Richard-Londt, A., Brandner, S., … &

Duchen, M. R. (2013). Mitochondria and quality control defects in a mouse model of Gaucher disease—links

to Parkinson’s disease. Cell metabolism, 17(6), 941-953.

90 Morciano, G., Patergnani, S., Bonora, M., Pedriali, G., Tarocco, A., Bouhamida, E., … & Pinton, P. (2020).

Mitophagy in cardiovascular diseases. Journal of clinical medicine, 9(3), 892.

91 Miao, M. Q., Han, Y. B., & Liu, L. (2023). Mitophagy in metabolic syndrome. The Journal of Clinical

Hypertension, 25(5), 397-403.

92 Park, J. H., Ko, J., Park, Y. S., Park, J., Hwang, J., & Koh, H. C. (2017). Clearance of damaged

mitochondria through PINK1 stabilization by JNK and ERK MAPK signaling in chlorpyrifos-treated

neuroblastoma cells. Molecular neurobiology, 54, 1844-1857.

93 (a) Chen, M., Chen, Z., Wang, Y., Tan, Z., Zhu, C., Li, Y., … & Chen, Q. (2016). Mitophagy receptor

FUNDC1 regulates mitochondrial dynamics and mitophagy. Autophagy, 12(4), 689-702. (b) Park, S. Y., &

Koh, H. C. (2020). FUNDC1 regulates receptor-mediated mitophagy independently of the PINK1/Parkin-

dependent pathway in rotenone-treated SH-SY5Y cells. Food and Chemical Toxicology, 137, 111163. (c)

He, H., Huang, W., Xiong, L., Ma, C., Wang, Y., Sun, P., … & Wu, Y. (2024). FUNDC1-mediated mitophagy

regulates photodamage independently of the PINK1/Parkin-dependent pathway. Free Radical Biology and

Medicine, 225, 630-640.

94 Majeski, A. E., & Dice, J. F. (2004). Mechanisms of chaperone-mediated autophagy. The international

journal of biochemistry & cell biology, 36(12), 2435-2444.

95 Xiong, Y., Contento, A. L., Nguyen, P. Q., & Bassham, D. C. (2007). Degradation of oxidized proteins by

autophagy during oxidative stress in Arabidopsis. Plant physiology, 143(1), 291-299.

96 Kiffin, R., Christian, C., Knecht, E., & Cuervo, A. M. (2004). Activation of chaperone-mediated autophagy

during oxidative stress. Molecular biology of the cell, 15(11), 4829-4840.

97 Cuervo, A. M., & Dice, J. F. (2000). Unique properties of lamp2a compared to other lamp2 isoforms.

Journal of cell science, 113(24), 4441-4450.

98 Zhang, Q., Kang, R., Zeh, III, H. J., Lotze, M. T., & Tang, D. (2013). DAMPs and autophagy: cellular

adaptation to injury and unscheduled cell death. Autophagy, 9(4), 451-458.

99 (a) Deretic, V. (2021). Autophagy in inflammation, infection, and immunometabolism. Immunity, 54(3),

437-453. (b) Tsuji, Y., Kuramochi, M., Golbar, H. M., Izawa, T., Kuwamura, M., & Yamate, J. (2020).

Acetaminophen-induced rat hepatotoxicity based on M1/M2-macrophage polarization, in possible relation

to damage-associated molecular patterns and autophagy. International Journal of Molecular

Sciences, 21(23), 8998. (c) Levy, J. M. M., Towers, C. G., & Thorburn, A. (2017). Targeting autophagy in

cancer. Nature Reviews Cancer, 17(9), 528-542.

100 Levine, B., Mizushima, N., & Virgin, H. W. (2011). Autophagy in immunity and inflammation. Nature,

469(7330), 323-335.101 Deretic, V., Saitoh, T., & Akira, S. (2013). Autophagy in infection, inflammation and immunity. Nature

Reviews Immunology, 13(10), 722-737.

102 Moore, M. N. (2020). Lysosomes, autophagy, and hormesis in cell physiology, pathology, and age-related

disease. Dose-Response, 18(3), 1559325820934227.

103 García-Prat, L., Martínez-Vicente, M., Perdiguero, E., Ortet, L., Rodríguez-Ubreva, J., Rebollo, E., … &

Muñoz-Cánoves, P. (2016). Autophagy maintains stemness by preventing senescence. Nature, 529(7584),

37-42.

104 Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., … &

Mizushima, N. (2006). Suppression of basal autophagy in neural cells causes neurodegenerative disease in

mice. Nature, 441(7095), 885-889.

105 Zapata-Muñoz, J., Villarejo-Zori, B., Largo-Barrientos, P., & Boya, P. (2021). Towards a better

understanding of the neuro-developmental role of autophagy in sickness and in health. Cell Stress, 5(7), 99.

106 Nixon, R. A. (2013). The role of autophagy in neurodegenerative disease. Nature medicine, 19(8), 983-

997.

107 Tomoda, T., Yang, K., & Sawa, A. (2020). Neuronal autophagy in synaptic functions and psychiatric

disorders. Biological psychiatry, 87(9), 787-796.

108 Sil, P., Wong, S. W., & Martinez, J. (2018). More than skin deep: autophagy is vital for skin barrier

function. Frontiers in immunology, 9, 1376.

109 Jeong, D., Qomaladewi, N. P., Lee, J., Park, S. H., & Cho, J. Y. (2020). The role of autophagy in skin

fibroblasts, keratinocytes, melanocytes, and epidermal stem cells. Journal of Investigative Dermatology,

140(9), 1691-1697.

110 Richmond, J. M., & Harris, J. E. (2014). Immunology and skin in health and disease. Cold Spring Harbor

perspectives in medicine, 4(12), a015339.

111 Pivarcsi, A., Nagy, I., & Kemeny, L. (2005). Innate immunity in the skin: how keratinocytes fight against

pathogens. Current immunology reviews, 1(1), 29-42.

112 Davidson, S., Coles, M., Thomas, T., Kollias, G., Ludewig, B., Turley, S., … & Buckley, C. D. (2021).

Fibroblasts as immune regulators in infection, inflammation and cancer. Nature Reviews Immunology,

21(11), 704-717.

113 Zhang, H., Xia, M., Li, H., Zeng, X., Jia, H., Zhang, W., & Zhou, J. (2025). Implication of

Immunobiological Function of Melanocytes in Dermatology. Clinical Reviews in Allergy & Immunology,

68(1), 30.

114 Jeong, D., Qomaladewi, N. P., Lee, J., Park, S. H., & Cho, J. Y. (2020). The role of autophagy in skin

fibroblasts, keratinocytes, melanocytes, and epidermal stem cells. Journal of Investigative Dermatology,

140(9), 1691-1697.

115 Ren, H., Zhao, F., Zhang, Q., Huang, X., & Wang, Z. (2022). Autophagy and skin wound healing. Burns

& trauma, 10, tkac003.

116 Li, X., Wu, J., Sun, X., Wu, Q., Li, Y., Li, K., … & Chen, H. (2020). Autophagy reprograms alveolar

progenitor cell metabolism in response to lung injury. Stem Cell Reports, 14(3), 420-432.

117 de la Vega, M. R., Dodson, M., Gross, C., Mansour, H. M., Lantz, R. C., Chapman, E., … & Zhang, D. D.

(2016). Role of Nrf2 and autophagy in acute lung injury. Current pharmacology reports, 2, 91-101.

118 Yin, X., Xin, H., Mao, S., Wu, G., & Guo, L. (2019). The role of autophagy in sepsis: protection and

injury to organs. Frontiers in physiology, 10, 1071.

119 Barnes, P. J., Baker, J., & Donnelly, L. E. (2022). Autophagy in asthma and chronic obstructive pulmonary

disease. Clinical Science, 136(10), 733-746.

120 Mizumura, K., Maruoka, S., Shimizu, T., & Gon, Y. (2018). Autophagy, selective autophagy, and

necroptosis in COPD. International journal of chronic obstructive pulmonary disease, 3165-3172.

121 Araya, J., Kojima, J., Takasaka, N., Ito, S., Fujii, S., Hara, H., … & Kuwano, K. (2013). Insufficient

autophagy in idiopathic pulmonary fibrosis. American Journal of Physiology-Lung Cellular and Molecular

Physiology, 304(1), L56-L69.

122 Patel, A. S., Lin, L., Geyer, A., Haspel, J. A., An, C. H., Cao, J., … & Morse, D. (2012). Autophagy in

idiopathic pulmonary fibrosis. PloS one, 7(7), e41394.

123 McAlinden, K. D., Deshpande, D. A., Ghavami, S., Xenaki, D., Sohal, S. S., Oliver, B. G., … & Sharma,

P. (2019). Autophagy activation in asthma airways remodeling. American journal of respiratory cell and

molecular biology, 60(5), 541-553.

124 Liu, C., Liu, Y., Chen, H., Yang, X., Lu, C., Wang, L., & Lu, J. (2023). Myocardial injury: where

inflammation and autophagy meet. Burns & Trauma, 11, tkac062.125 Alcalai, R., Arad, M., Wakimoto, H., Yadin, D., Gorham, J., Wang, L., … & Seidman, C. E. (2021).

LAMP2 cardiomyopathy: consequences of impaired autophagy in the heart. Journal of the American Heart

Association, 10(17), e018829.

126 Liu, Y., Wang, Y., Bi, Y., Zhao, Z., Wang, S., Lin, S., … & Mao, J. (2023). Emerging role of mitophagy

in heart failure: from molecular mechanism to targeted therapy. Cell Cycle, 22(8), 906-918.

127 Shen, Y., Liu, X., Shi, J., & Wu, X. (2019). Involvement of Nrf2 in myocardial ischemia and reperfusion

injury. International journal of biological macromolecules, 125, 496-502.

128 Chen, X., Ji, Y., Liu, R., Zhu, X., Wang, K., Yang, X., … & Sun, H. (2023). Mitochondrial dysfunction:

roles in skeletal muscle atrophy. Journal of Translational Medicine, 21(1), 503.

129 Li, P., Ma, Y., Yu, C., Wu, S., Wang, K., Yi, H., & Liang, W. (2021). Autophagy and aging: Roles in

skeletal muscle, eye, brain and hepatic tissue. Frontiers in Cell and Developmental Biology, 9, 752962.

130 Ferraro, E., Giammarioli, A. M., Chiandotto, S., Spoletini, I., & Rosano, G. (2014). Exercise-induced

skeletal muscle remodeling and metabolic adaptation: redox signaling and role of autophagy. Antioxidants

& redox signaling, 21(1), 154-176.

131 Weckman, A., Di Ieva, A., Rotondo, F., Syro, L. V., Ortiz, L. D., Kovacs, K., & Cusimano, M. D. (2014).

Autophagy in the endocrine glands. J Mol Endocrinol, 52(2), R151-R163.

132 (a) Afzal, A., Zhang, Y., Afzal, H., Saddozai, U. A. K., Zhang, L., Ji, X. Y., & Khawar, M. B. (2024).

Functional role of autophagy in testicular and ovarian steroidogenesis. Frontiers in Cell and Developmental

Biology, 12, 1384047. (b) Xu, R., Wang, F., Zhang, Z., Zhang, Y., Tang, Y., Bi, J., … & Tang, Z. (2023).

Diabetes‐induced autophagy dysregulation engenders testicular impairment via oxidative stress. Oxidative

medicine and cellular longevity, 2023(1), 4365895.

133 (a) Kong, X., Wang, X., Xia, Q., Hu, Q., Yu, W., Huang, Q., … & Yu, J. (2025). Unveiling the nexus

between environmental exposures and testicular damages: revelations from autophagy and oxidative stress

imbalance. Cell Death Discovery, 11(1), 258. (b) Jung, H. S., & Lee, M. S. (2010). Role of autophagy in

diabetes and mitochondria. Annals of the New York Academy of Sciences, 1201(1), 79-83.

134 Zhao, X., Jiang, Y., Jiang, T., Han, X., Wang, Y., Chen, L., & Feng, X. (2020). Physiological and

pathological regulation of autophagy in pregnancy. Archives of Gynecology and Obstetrics, 302(2), 293-303.

135 Chen, H., Chen, Y., & Zheng, Q. (2024). The regulated cell death at the maternal-fetal interface: beneficial

or detrimental?. Cell Death Discovery, 10(1), 100.

136 Zhou, P., Wang, J., Wang, J., & Liu, X. (2024). When autophagy meets placenta development and

pregnancy complications. Frontiers in Cell and Developmental Biology, 12, 1327167.

137 Wang, Y., Singh, R., Xiang, Y., & Czaja, M. J. (2010). Macroautophagy and chaperone‐mediated

autophagy are required for hepatocyte resistance to oxidant stress. Hepatology, 52(1), 266-277.

138 Xu, F., Hua, C., Tautenhahn, H. M., Dirsch, O., & Dahmen, U. (2020). The role of autophagy for the

regeneration of the aging liver. International journal of molecular sciences, 21(10), 3606.

139 (a) Cursio, R., Colosetti, P., Codogno, P., Cuervo, A. M., & Shen, H. M. (2015). The role of autophagy

in liver diseases: mechanisms and potential therapeutic targets. BioMed Research International, 2015,

480508. (b) Ruart, M., Chavarria, L., Campreciós, G., Suárez-Herrera, N., Montironi, C., Guixé-Muntet, S.,

… & Hernández-Gea, V. (2019). Impaired endothelial autophagy promotes liver fibrosis by aggravating the

oxidative stress response during acute liver injury. Journal of hepatology, 70(3), 458-469.

140 Jaganjac, M., Milkovic, L., Zarkovic, N., & Zarkovic, K. (2022). Oxidative stress and regeneration. Free

Radical Biology and Medicine, 181, 154-165.

141 Franzini, M., Valdenassi, L., Pandolfi, S., Tirelli, U., Ricevuti, G., & Chirumbolo, S. (2023). The role of

ozone as an Nrf2-keap1-ARE activator in the anti-microbial activity and immunity modulation of infected

wounds. Antioxidants, 12(11), 1985.

142 Clavo, B., Rodríguez-Esparragón, F., Rodríguez-Abreu, D., Martínez-Sánchez, G., Llontop, P., Aguiar-

Bujanda, D., … & Santana-Rodríguez, N. (2019). Modulation of oxidative stress by ozone therapy in the

prevention and treatment of chemotherapy-induced toxicity: review and prospects. Antioxidants, 8(12), 588.

143 Zielinski, M. R., McKenna, J. T., & McCarley, R. W. (2016). Functions and mechanisms of sleep. AIMS

neuroscience, 3(1), 67.

144 Peliciari-Garcia, R. A., Darley-Usmar, V., & Young, M. E. (2018). An overview of the emerging interface

between cardiac metabolism, redox biology and the circadian clock. Free radical biology and medicine, 119,

75-84.

145 (a) Reimund, E. (1994). The free radical flux theory of sleep. Medical hypotheses, 43(4), 231-233. (b)

Villafuerte, G., Miguel-Puga, A., Murillo Rodríguez, E., Machado, S., Manjarrez, E., & Arias-Carrión, O.(2015). Sleep deprivation and oxidative stress in animal models: a systematic review. Oxidative medicine

and cellular longevity, 2015(1), 234952.

146 (a) Bryndin, E., & Bryndina, I. (2020). Self healing of healthy condition at cellular level. Medical Case

Reports and Reviews, 3, 1-4. (b) Adam, K., & Oswald, I. (1984). Sleep helps healing. British medical journal

(Clinical research ed.), 289(6456), 1400.

147 (a) Garbarino, S., Lanteri, P., Bragazzi, N. L., Magnavita, N., & Scoditti, E. (2021). Role of sleep

deprivation in immune-related disease risk and outcomes. Communications biology, 4(1), 1304. (b)

Tobaldini, E., Costantino, G., Solbiati, M., Cogliati, C., Kara, T., Nobili, L., & Montano, N. (2017). Sleep,

sleep deprivation, autonomic nervous system and cardiovascular diseases. Neuroscience & Biobehavioral

Reviews, 74, 321-329.

148 Wilking, M., Ndiaye, M., Mukhtar, H., & Ahmad, N. (2013). Circadian rhythm connections to oxidative

stress: implications for human health. Antioxidants & redox signaling, 19(2), 192-208.

149 Atrooz, F., & Salim, S. (2020). Sleep deprivation, oxidative stress and inflammation. Advances in protein

chemistry and structural biology, 119, 309-336.

150 Patki, G., Solanki, N., Atrooz, F., Allam, F., & Salim, S. (2013). Depression, anxiety-like behavior and

memory impairment are associated with increased oxidative stress and inflammation in a rat model of social

stress. Brain research, 1539, 73-86.

151 Mattson, M. P. (2008). Hormesis defined. Ageing research reviews, 7(1), 1-7.

152 Besedovsky, L., Lange, T., & Haack, M. (2019). The sleep-immune crosstalk in health and disease.

Physiological reviews.

153 (a) Deary, V., Ellis, J. G., Wilson, J. A., Coulter, C., & Barclay, N. L. (2014). Simple snoring: not quite

so simple after all?. Sleep medicine reviews, 18(6), 453-462. (b) Sarkis, L. M., Jones, A. C., Ng, A., Pantin,

C., Appleton, S. L., & MacKay, S. G. (2023). Australasian Sleep Association position statement on consensus

and evidence based treatment for primary snoring. Respirology, 28(2), 110-119.

154 Gonzalez-Rothi, E. J., Lee, K. Z., Dale, E. A., Reier, P. J., Mitchell, G. S., & Fuller, D. D. (2015).

Intermittent hypoxia and neurorehabilitation. Journal of applied physiology, 119(12), 1455-1465.

155 Swart, M. L., Van Schagen, A. M., Lancee, J., & Van Den Bout, J. (2013). Prevalence of nightmare

disorder in psychiatric outpatients. Psychotherapy and psychosomatics, 82(4), 267-268.

156 (a) Levin, R., & Nielsen, T. A. (2007). Disturbed dreaming, posttraumatic stress disorder, and affect

distress: a review and neurocognitive model. Psychological bulletin, 133(3), 482. (b) Gieselmann, A., Ait

Aoudia, M., Carr, M., Germain, A., Gorzka, R., Holzinger, B., … & Pietrowsky, R. (2019). Aetiology and

treatment of nightmare disorder: State of the art and future perspectives. Journal of sleep research, 28(4),

e12820.

157 Krakow, B., & Zadra, A. (2006). Clinical management of chronic nightmares: imagery rehearsal therapy.

Behavioral Sleep Medicine, 4(1), 45–70.

158 Germain, A., Buysse, D. J., & Nofzinger, E. (2008). Sleep-specific mechanisms underlying posttraumatic

stress disorder: integrative review and neurobiological hypotheses. Sleep medicine reviews, 12(3), 185-195.

159 Hsieh, C. F., Huang, C. T., Chang, C. C., & Hung, T. P. (2025). Singlet Oxygen Energy for Enhancing

Physiological Function and Athletic Performance. Bioengineering, 12(2), 118.

160 Martinez-Canton, M., Galvan-Alvarez, V., Martin-Rincon, M., Calbet, J. A., & Gallego-Selles, A. (2024).

Unlocking peak performance: The role of Nrf2 in enhancing exercise outcomes and training adaptation in

humans. Free Radical Biology and Medicine, 224, 168-181.

161 Taskin, S., Celik, T., Demiryurek, S., Turedi, S., & Taskin, A. (2022). Effects of different-intensity

exercise and creatine supplementation on mitochondrial biogenesis and redox status in mice. Iranian Journal

of Basic Medical Sciences, 25(8), 1009.

162 Sun, Y., Jin, L., Qin, Y., Ouyang, Z., Zhong, J., & Zeng, Y. (2024). Harnessing mitochondrial stress for

health and disease: Opportunities and challenges. Biology, 13(6), 394.

163 Viollet, B. (2017). The energy sensor AMPK: adaptations to exercise, nutritional and hormonal signals.

Hormones, metabolism and the benefits of exercise, 13.

164 Meng, Q., & Su, C. H. (2024). The impact of physical exercise on oxidative and nitrosative stress:

balancing the benefits and risks. Antioxidants, 13(5), 573.

165 Sockrider, M., & Fussner, L. (2020). What is asthma?. American journal of respiratory and critical care

medicine, 202(9), P25-P26.

166 Venkatesan, P. (2023). 2023 GINA report for asthma. The Lancet Respiratory Medicine, 11(7), 589.

167 To be published168 Adeloye, D., Song, P., Zhu, Y., Campbell, H., Sheikh, A., & Rudan, I. (2022). Global, regional, and

national prevalence of, and risk factors for, chronic obstructive pulmonary disease (COPD) in 2019: a

systematic review and modelling analysis. The Lancet Respiratory Medicine, 10(5), 447-458.

169 Erpenbach, K. H., Brailey, M. A., & Stentiford, N. Bronchial Asthma and Chronic Obstructive Lung

Diseases: Improvement of the 6. minute walking test and the lung function by inhaling activated air produced

by the SOE. TIE therapeutic inhalation equipment.

170 Duan, K. I., Birger, M., Au, D. H., Spece, L. J., Feemster, L. C., & Dieleman, J. L. (2023). Health Care

Spending on Respiratory Diseases in the United States, 1996–2016. American Journal of Respiratory and

Critical Care Medicine, 207(2), 183-192.

171 Paulson, K. R., Kamath, A. M., Alam, T., Bienhoff, K., Abady, G. G., Abbas, J., … & Chanie, W. F.

(2021). Global, regional, and national progress towards Sustainable Development Goal 3.2 for neonatal and

child health: all-cause and cause-specific mortality findings from the Global Burden of Disease Study

2019. The Lancet, 398(10303), 870-905.

172 Gordon, B. R. (2008). Asthma history and presentation. Otolaryngologic Clinics of North America, 41(2),

375-385.

173 Burgel, P. R. (2012). Chronic cough and sputum production: a clinical COPD phenotype?. European

Respiratory Journal, 40(1), 4-6.

174 Diehr, P., Wood, R. W., Bushyhead, J., Krueger, L., Wolcott, B., & Tompkins, R. K. (1984). Prediction

of pneumonia in outpatients with acute cough—a statistical approach. Journal of chronic diseases, 37(3),

215-225.

175 Tollerud, D. J., O’connor, G. T., Sparrow, D., & Weiss, S. T. (1991). Asthma, hay fever, and phlegm

production associated with distinct patterns of allergy skin test reactivity, eosinophilia, and serum IgE levels.

The Normative Aging Study. Am Rev Respir Dis, 144(4), 776-81.

176 Heijdra, Y. F., Pinto-Plata, V. M., Kenney, L. A., Rassulo, J., & Celli, B. R. (2002). Cough and phlegm

are important predictors of health status in smokers without COPD. Chest, 121(5), 1427-1433.

177 (a) Pitts, T., Bolser, D., Rosenbek, J., Troche, M., & Sapienza, C. (2008). Voluntary cough production

and swallow dysfunction in Parkinson’s disease. Dysphagia, 23, 297-301. (b) Heijdra, Y. F., Pinto-Plata, V.

M., Kenney, L. A., Rassulo, J., & Celli, B. R. (2002). Cough and phlegm are important predictors of health

status in smokers without COPD. Chest, 121(5), 1427-1433. (c) Davies, D. (1974). Disability and coal

workers’ pneumoconiosis. British medical journal, 2(5920), 652. (d) Warren, C. P. (1979). Acute respiratory

failure and tracheal obstruction in the elderly with benign goitres. Canadian Medical Association

Journal, 121(2), 191.

178 Whitsett, J. A., & Alenghat, T. (2015). Respiratory epithelial cells orchestrate pulmonary innate immunity.

Nature immunology, 16(1), 27-35.

179 Voynow, J. A., & Rubin, B. K. (2009). Mucins, mucus, and sputum. Chest, 135(2), 505-512.

180 (a) Biswas, S. K., & Rahman, I. (2009). Environmental toxicity, redox signaling and lung inflammation:

the role of glutathione. Molecular aspects of medicine, 30(1-2), 60-76. (b) Shao, M. X., & Nadel, J. A. (2005).

Dual oxidase 1-dependent MUC5AC mucin expression in cultured human airway epithelial cells.

Proceedings of the National Academy of Sciences, 102(3), 767-772.

181 Price, M. E., & Sisson, J. H. (2019). Redox regulation of motile cilia in airway disease. Redox Biology,

27, 101146.

182 Rancourt, R. C., Lee, R. L., O’Neill, H., Accurso, F. J., & White, C. W. (2007). Reduced thioredoxin

increases proinflammatory cytokines and neutrophil influx in rat airways: modulation by airway mucus. Free

Radical Biology and Medicine, 42(9), 1441-1453.

183 Zhang, M., Wang, J., Liu, R., Wang, Q., Qin, S., Chen, Y., & Li, W. (2024). The role of Keap1-Nrf2

signaling pathway in the treatment of respiratory diseases and the research progress on targeted drugs.

Heliyon.

184 (a) Barnes, P. J. (2008). The cytokine network in asthma and chronic obstructive pulmonary disease. The

Journal of clinical investigation, 118(11), 3546-3556. (b) Xu, W., Zhao, T., & Xiao, H. (2020). The

implication of oxidative stress and AMPK-Nrf2 antioxidative signaling in pneumonia pathogenesis. Frontiers

in Endocrinology, 11, 400.

185 Kume, H., Yamada, R., Sato, Y., & Togawa, R. (2023). Airway smooth muscle regulated by oxidative

stress in COPD. Antioxidants, 12(1), 142.

186 Michaeloudes, C., Abubakar-Waziri, H., Lakhdar, R., Raby, K., Dixey, P., Adcock, I. M., … & Chung, K.

F. (2022). Molecular mechanisms of oxidative stress in asthma. Molecular aspects of medicine, 85, 101026.187 (a) Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z., … & Cao, B. (2020). Clinical course and risk factors

for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The lancet,

395(10229), 1054-1062. (b) George, P. M., Barratt, S. L., Condliffe, R., Desai, S. R., Devaraj, A., Forrest, I.,

… & Spencer, L. G. (2020). Respiratory follow-up of patients with COVID-19 pneumonia. Thorax, 75(11),

1009-1016.

188 Wu, Z., & McGoogan, J. M. (2020). Characteristics of and important lessons from the coronavirus disease

2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for

Disease Control and Prevention. jama, 323(13), 1239-1242.

189 “Post COVID-19 condition (long COVID).” World Health Organization (WHO), 26 February 2025,

https://www.who.int/news-room/fact-sheets/detail/post-covid-19-condition-(long-covid). Accessed 2

August 2025.

190 (a) Nalbandian, A., Sehgal, K., Gupta, A., Madhavan, M. V., McGroder, C., Stevens, J. S., … & Wan, E.

Y. (2021). Post-acute COVID-19 syndrome. Nature medicine, 27(4), 601-615. (b) Yong, S. J. (2021).

Persistent brainstem dysfunction in long-COVID: a hypothesis. ACS chemical neuroscience, 12(4), 573-580.

191 World Health Organization. (2023). Accelerating anaemia reduction: Acomprehensive framework for

action. World Health Organization.

192 Weiss, G., Ganz, T., & Goodnough, L. T. (2019). Anemia of inflammation. Blood, The Journal of the

American Society of Hematology, 133(1), 40-50.

193 Shaw, P., & Chattopadhyay, A. (2020). Nrf2–ARE signaling in cellular protection: Mechanism of action

and the regulatory mechanisms. Journal of Cellular Physiology, 235(4), 3119-3130.

194 Dewhirst, M. W. (2009). Relationships between cycling hypoxia, HIF-1, angiogenesis and oxidative

stress. Radiation research, 172(6), 653-665.

195 Wang, J., & Pantopoulos, K. (2011). Regulation of cellular iron metabolism. Biochemical Journal, 434(3),

365-381.

196 ORINO, K., LEHMAN, L., TSUJI, Y., AYAKI, H., TORTI, S. V., & TORTI, F. M. (2001). Ferritin and

the response to oxidative stress. Biochemical Journal, 357(1), 241-247.

197 Wilson, B. E., Jacob, S., Yap, M. L., Ferlay, J., Bray, F., & Barton, M. B. (2019). Estimates of global

chemotherapy demands and corresponding physician workforce requirements for 2018 and 2040: a

population-based study. The Lancet Oncology, 20(6), 769-780.

198 Sano, M., & Fukuda, K. (2008). Activation of mitochondrial biogenesis by hormesis. Circulation research,

103(11), 1191-1193.

199 Clavo, B., Rodríguez-Esparragón, F., Rodríguez-Abreu, D., Martínez-Sánchez, G., Llontop, P., Aguiar-

Bujanda, D., … & Santana-Rodríguez, N. (2019). Modulation of oxidative stress by ozone therapy in the

prevention and treatment of chemotherapy-induced toxicity: review and prospects. Antioxidants, 8(12), 588.

200 Li, N., & Karin, M. (1999). Is NF‐κB the sensor of oxidative stress?. The FASEB Journal, 13(10), 1137-

1143.

201 (a) Pradat, P. F., & Delanian, S. (2013). Late radiation injury to peripheral nerves. Handbook of clinical

neurology, 115, 743-758. (b) Pariset, E., Malkani, S., Cekanaviciute, E., & Costes, S. V. (2021). Ionizing

radiation-induced risks to the central nervous system and countermeasures in cellular and rodent models.

International Journal of Radiation Biology, 97(sup1), S132-S150. (c) Azzam, P., Mroueh, M., Francis, M.,

Abou Daher, A., & Zeidan, Y. H. (2020). Radiation-induced neuropathies in head and neck cancer:

prevention and treatment modalities. ecancermedicalscience, 14, 1133.

202 Yoon, K. C., Jeong, I. Y., Park, Y. G., & Yang, S. Y. (2007). Interleukin-6 and tumor necrosis factor-α

levels in tears of patients with dry eye syndrome. Cornea, 26(4), 431-437.

203 Pflugfelder, S. C., & de Paiva, C. S. (2017). The pathophysiology of dry eye disease: what we know and

future directions for research. Ophthalmology, 124(11), S4-S13.

204 Böhm, E. W., Buonfiglio, F., Voigt, A. M., Bachmann, P., Safi, T., Pfeiffer, N., & Gericke, A. (2023).

Oxidative stress in the eye and its role in the pathophysiology of ocular diseases. Redox biology, 68, 102967.

205 Grimwood, S. J. (2024). Profiling the Physiological and Psychological Effectiveness of Singlet Oxygen

in the Management of Chronic Obstructive Pulmonary Disease (COPD) (Doctoral dissertation, University of

Derby (United Kingdom)).

206 (a) Price, D. D., Finniss, D. G., & Benedetti, F. (2008). A comprehensive review of the placebo effect:

recent advances and current thought. Annu. Rev. Psychol., 59(1), 565-590. (b) Enck, P., Benedetti, F., &

Schedlowski, M. (2008). New insights into the placebo and nocebo responses. Neuron, 59(2), 195-206.207 (a) Colloca, L., & Barsky, A. J. (2020). Placebo and nocebo effects. New England Journal of Medicine,

382(6), 554-561. (b) Benedetti, F., & Amanzio, M. (2013). Mechanisms of the placebo response. Pulmonary

pharmacology & therapeutics, 26(5), 520-523.

208 Liu, S., Pi, J., & Zhang, Q. (2022).