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Background and Objectives: The main neurodegenerative diseases (NDs)—Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS)—represent a growing global health burden with no available disease-modifying therapies. Curcumin, a polyphenol from Curcuma longa, is a promising candidate owing to its pleiotropic antioxidant, anti-inflammatory, and neuroprotective profile observed mainly in preclinical models, but the poor oral bioavailability (<1%) and negligible BBB penetration (<0.1%) have substantially limited curcumin’s clinical translation. The objective of this work was to critically examine the therapeutic potential of curcumin in NDs, focusing on advanced drug delivery systems (DDSs) designed to overcome its pharmacokinetic barriers. Methods: This is a narrative, non-systematic review of PubMed/MEDLINE, Scopus, and Web of Science. The review is organized around five complementary thematic areas selected to span the full translational pipeline of curcumin in neurodegeneration, from mechanistic rationale to clinical applicability: (1) molecular mechanisms, addressing the pleiotropic activities that justify therapeutic interest; (2) pharmacokinetic barriers, the principal obstacle to clinical translation; (3) the evolution of drug delivery systems (DDSs), documenting the technological strategies developed to overcome these barriers; (4) disease-specific applications, evaluating the available evidence across the four main NDs; and (5) translational limitations, identifying the methodological and regulatory gaps that must be closed to enable clinical implementation. Results: Curcumin exhibits neuroprotective activity in preclinical models of the four NDs analysed, acting on six interconnected mechanisms and the gut–brain axis. Four generations of DDSs have been developed, from phytosomes and clinically used lipid dispersions (Meriva^®, BCM-95^®, Longvida^®, and Theracurmin^®) to fourth-generation systems (biomimetic nanoparticles, MOFs, microneedles, 3D scaffolds, hydrogels, and carbon dots) that substantially increase the bioavailability in preclinical studies. Combination strategies, such as curcumin with resveratrol and dutasteride, show preliminary clinical signals in ALS. However, clinical translation remains limited: over 80% of positive animal findings have not been replicated in humans, formulation characterization is frequently incomplete, and most trials lack CNS-exposure biomarkers. Importantly, most of the reported bioavailability claims are based on total curcumin measurements (parent aglycone plus its inactive Phase II conjugates) rather than the active aglycone alone, a methodological limitation that should be considered when interpreting the magnitude of the bioavailability improvements reported for novel formulations. Conclusions: Curcumin exhibits pleiotropic neuroprotective activity in preclinical models of AD, PD, MS, and ALS, mediated by interconnected antioxidant, anti-inflammatory, anti-amyloidogenic, mitochondrial, and gut–brain axis mechanisms. However, its poor systemic bioavailability (<1%), minimal blood–brain barrier penetration, and extensive first-pass metabolism have limited clinical translation. Advanced drug delivery systems (including lipid-based carriers (liposomes, solid lipid nanoparticles, and nanostructured lipid carriers), polymeric nanoparticles (PLGA and chitosan), and bioinspired vesicles (exosomes)) are essential in order to overcome these barriers. Nevertheless, the formulation heterogeneity, limited long-term safety data, and reliance on preclinical models remain major obstacles; a definitive clinical translation will therefore require well-characterized formulations validated in phase II/III trials with cerebrospinal fluid exposure biomarkers, the pharmacokinetic monitoring of active aglycone (rather than total curcumin including inactive conjugates), and adaptive trial designs in neurological populations. Full article

Intrauterine adhesion (IUA) is a fibrotic disorder resulting from aberrant repair following injury to the endometrial basal layer, leading to menstrual abnormalities, infertility, recurrent miscarriage, and pregnancy complications. Although hysteroscopic adhesiolysis remains the primary clinical treatment, the rate of postoperative re–adhesion is still high, especially in patients with moderate–to–severe IUA. Moreover, mechanical separation alone is often insufficient to restore intact endometrial architecture and reproductive function. Hydrogels, with their hydrated three–dimensional networks, extracellular matrix (ECM)–mimicking properties, injectability, biodegradability, tissue adhesion, and tunable delivery capacity, have evolved from passive barrier materials into multifunctional therapeutic platforms capable of regulating the pathological microenvironment and promoting tissue regeneration. Recent advances in responsive, self–healing, adhesive, antioxidant, and bioactive cargo–loaded hydrogels have expanded their applications from preventing adhesion formation toward functional endometrial reconstruction. In this review, we summarize recent progress in hydrogel–based IUA therapy, focusing on material composition, structural design, functional modification, therapeutic mechanisms, and translational considerations. Particular emphasis is placed on disease–informed hydrogel engineering strategies that integrate the unique anatomical characteristics of the uterine cavity, injury–associated microenvironment, and dynamic stages of endometrial repair. This perspective provides insights into the development of next–generation hydrogel systems for preventing re–adhesion and restoring reproductive function. Full article

Background: Postpartum hypogalactia is a prevalent obstetric complication worldwide, closely associated with excessive oxidative stress and impaired antioxidant defense in mammary tissue. Current hormone-based therapies carry endocrine disruption risks, while natural antioxidant bioactive agents such as extracellular vesicles (EVs) are largely limited by rapid in vivo clearance and poor tissue retention. Methods: We constructed an injectable gelatin methacryloyl (GelMA) hydrogel system to encapsulate chemically induced mammary epithelial cell-derived EVs (CiMECs-EVs) and systematically evaluated their antioxidant and lactogenic activities via multi-omics analysis, cellular functional assays and a bromocriptine-induced murine hypogalactia model. Results: CiMECs-EVs induced a functional mammary epithelial-like phenotype in fibroblasts in a dose-dependent manner with functional cargo enriched in glutathione metabolism and redox-regulatory miRNAs. The GelMA matrix protected EV integrity and enabled sustained release, and the composite system significantly ameliorated mammary duct structure and lactation function in vivo with specific mammary tropism and no systemic toxicity, outperforming free EV treatment. Conclusions: This study presents a safe protein biomacromolecule-based antioxidant delivery platform that effectively restores mammary redox balance and antioxidant defenses, providing a promising non-hormonal therapeutic strategy for postpartum hypogalactia. Full article

Doxorubicin (DOX) is an antineoplastic agent commonly used in cancer therapy that is known for its testicular toxicity. DOX-induced testicular injury involves inflammation, reactive oxygen species, and oxidative stress. Centella asiatica exhibits anti-inflammatory and antioxidant properties. The present experimental study aimed to determine the potential protective efficacy of Centella asiatica in a rat model of doxorubicin-induced testicular toxicity. Rats were randomly assigned to four groups: healthy control (HC), CA, DOX, and CA + DOX (CADX). An oral dose of 200 mg/kg Centella asiatica was administered to the CA and CADX groups. The HC and DOX groups received saline. One hour later, DOX (7.5 mg/kg) was intraperitoneally injected into the DOX and CADX groups on days 1, 4, and 7. Centella asiatica markedly attenuated the DOX-induced increase in malondialdehyde, nitric oxide, and pro-inflammatory cytokine levels, while preventing the decrease in superoxide dismutase activity in testicular tissue (p < 0.001). Centella asiatica reduced the severity of DOX-induced morphological damage in testicular tissue (p < 0.05). Moreover, it partially restored reproductive hormone function. In conclusion, Centella asiatica demonstrates significant potential in mitigating DOX-induced oxidative damage, attenuating testicular injury and preserving the functional integrity of the male reproductive system. Full article

Uveitis comprises a heterogeneous group of intraocular inflammatory diseases that differ in anatomical location, etiology, clinical course, and immune mechanisms. Despite this diversity, evidence derived predominantly from experimental autoimmune uveitis (EAU) suggests that oxidative stress may act as a context-dependent amplifier linking immune activation, ocular barrier dysfunction, and tissue injury. Excess reactive oxygen species (ROS) disrupt redox homeostasis and activate redox-sensitive inflammatory signaling, thereby amplifying cytokine production, mitochondrial dysfunction, leukocyte recruitment, and retinal damage. This review summarizes current evidence on oxidative stress in uveitis, focusing on major ROS-generating systems, NF-κB-driven inflammation, Nrf2/HO-1-mediated antioxidant responses, MAPK and PI3K-Akt signaling, and immune–metabolic pathways involved in autoimmune ocular inflammation. Cell-specific responses in retinal and immune cells further illustrate how redox imbalance may contribute to local tissue injury and immune-mediated disease progression. The role of oxidative stress in blood–ocular barrier dysfunction, particularly blood–retinal barrier disruption during posterior segment inflammation, is also discussed. Overall, preclinical studies support an active role for oxidative stress in inflammatory amplification and ocular tissue injury, whereas evidence from patients with defined uveitic entities remains limited, heterogeneous, and largely associative. Redox-directed treatments should therefore currently be regarded as investigational adjunctive strategies rather than established therapies for uveitis. Full article

Cigarette smoke exposure is a major preventable risk factor for respiratory disease and drives oxidative and inflammatory lung injury, highlighting the urgent need for safe, multi-target interventions beyond conventional anti-inflammatory therapy. Formononetin (FMN), a naturally occurring isoflavone with antioxidant, anti-inflammatory, and microbiota-modulating potential, may offer a dietary-botanical strategy against smoke-related pulmonary damage. This study evaluated FMN against cigarette smoke extract (CSE)-induced lung injury and explored its associations with intestinal barrier integrity, gut microbiota, taurine metabolism, SLC6A6 expression, and NF-κB activation. In a CSE-challenged mouse model, oral FMN, particularly at 70 mg/kg, improved body weight gain, reduced the lung index, attenuated pulmonary histopathological injury, restored GSH/GSSG and SOD, decreased MDA, and suppressed TNF-α, IL-1β, and IL-6 expression. FMN also ameliorated colonic injury and restored ZO-1 and occludin expression. Exploratory 16S rRNA sequencing and fecal metabolomics indicated FMN-associated alterations in gut microbial composition and metabolic profiles, with taurine and hypotaurine metabolism identified as a candidate pathway for further investigation. FMN further restored lung taurine content and SLC6A6 expression while inhibiting NF-κB activation. These findings suggest that FMN alleviates CSE-induced lung injury and that this improvement is associated with coordinated changes in gut microbiota composition, taurine metabolism, SLC6A6 expression, and NF-κB activation. Full article

Peutz–Jeghers syndrome (PJS) presents an apparent biological paradox: heterozygous germline pathogenic variants in STK11 predispose to predominantly benign hamartomatous growth while conferring a markedly elevated lifetime risk of cancer, whereas somatic STK11 inactivation in established tumors is frequently associated with aggressive progression and therapeutic resistance. STK11 encodes liver kinase B1 (LKB1), a serine/threonine kinase that integrates metabolic, oxidative, architectural, and immune stress responses. Rather than acting solely as a direct brake on proliferation, LKB1 couples cellular growth, survival, and tissue organization to environmental fitness. We therefore propose a context-dependent stress adaptation framework in which impairment of STK11/LKB1 signaling relaxes stress-imposed constraints on cellular fitness, while the ultimate biological outcome is determined by allelic status, tissue context, and cooperating genetic alterations. In PJS, a heterozygous germline STK11 pathogenic variant creates a constitutional cancer predisposed state in which one functional allele is initially retained, although subsequent loss or impairment of the remaining allele may occur during tumor evolution. In sporadic cancers, somatic STK11 inactivation is often biallelic and frequently cooperates with alterations in KRAS, KEAP1, TP53, NF1, or PI3K-pathway genes. These genetic contexts can promote metabolic reprogramming, redox adaptation, autophagy dependence, immune exclusion, cellular plasticity, and therapeutic resistance, with the strongest mechanistic and clinical evidence currently derived from lung adenocarcinoma (LUAD). Within this framework, enhanced persistence under metabolic, oxidative, immune, and therapy-induced stress does not exclude proliferative effects of STK11 loss but provides a permissive background upon which cooperating oncogenic programs can drive clonal expansion and malignant progression. Stress adaptation creates dependencies on interconnected buffering systems, including antioxidant defenses, autophagy, metabolic plasticity, and ferroptosis suppression. Therapeutic strategies that simultaneously disrupt multiple compensatory pathways may therefore exceed tumor adaptive capacity, convert stress tolerance into therapeutic vulnerability, and provide a rational framework for treating LKB1-deficient tumors and other stress-adapted cancers. Full article

Cancer therapy-related cardiotoxicity has emerged as a major challenge in contemporary oncology, particularly in long-term survivors of childhood malignancies. Oxidative stress (OS)-induced cardiotoxicity represents a key mechanistic pathway underlying myocardial injury caused by numerous anti-neoplastic drugs, most notably anthracycline-based chemotherapy, while OS also critically contributes to radiotherapy-induced cardiotoxicity. Excessive reactive oxygen and nitrogen species generation promotes mitochondrial dysfunction, impaired calcium homeostasis, lipid peroxidation, endothelial injury, inflammatory activation, and cardiomyocyte apoptosis, ultimately leading to progressive cardiac remodeling and ventricular dysfunction. These processes are of particular concern in pediatric cancer survivors, especially children treated for leukemia, who face a substantially elevated lifetime risk of cardiovascular disease following treatment exposure. Increasing attention has, therefore, been directed toward nutritional strategies capable of modulating redox homeostasis and attenuating treatment-associated myocardial injury. Experimental and translational evidence suggests that selected dietary compounds and nutraceuticals, including polyphenols, omega-3 fatty acids, coenzyme Q10, selenium, antioxidant vitamins, nutrition-based epigenetic interventions and intestinal microbiota composition modulations may exert cardioprotective effects through preservation of mitochondrial integrity, enhancement of endogenous antioxidant defenses, and suppression of oxidative and inflammatory signaling pathways. Nevertheless, clinical implementation remains limited by insufficient standardization, heterogeneous study designs, and incomplete understanding of long-term efficacy and safety. This narrative review critically examines the molecular basis of the OS-induced cardiotoxicity and radiotherapy-induced cardiotoxicity and evaluates current evidence supporting nutrition-based cardioprotective interventions, with particular emphasis on pediatric leukemia survivors and the prevention of long-term cardiovascular complications following anticancer therapy. Full article

Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy (prevalence ~1:4000) and a leading Mendelian cause of working-age blindness. Despite marked genetic heterogeneity, its progression converges on a common secondary cascade of outer-retinal hyperoxia, increased reactive oxygen species (ROS), and mitochondrial dysfunction that drives cone degeneration and central vision loss. Because this oxidative cascade is largely genotype-independent and pharmacologically tractable, oxidative stress is a cross-cutting therapeutic target. Within it, mitochondrial DNA (mtDNA) is a key element: once released from damaged photoreceptors—free or within exosomes—it may act as a damage-associated molecular pattern (DAMP), engaging TLR9, cGAS–STING, and the NLRP3 inflammasome and sustaining chronic neuroinflammation. Extracellular mtDNA is therefore a potential integrative marker, simultaneously reflecting oxidative stress, mitochondrial dysfunction, cell death, and innate-immune activation. A central knowledge gap, however, remains: the mechanistic steps linking mtDNA to inflammation and to photoreceptor death have not been demonstrated in RP itself, and extracellular mtDNA has never been quantified in the ocular fluids of RP patients. In this review we appraise oxidative biomarkers in RP, propose extracellular mtDNA as a candidate biomarker of disease activity, and examine antioxidant and redox-modulating therapies—from N-acetylcysteine and elamipretide trials to DAMP-sensor inhibition—across experimental and clinical models. Finally, we propose extracellular mtDNA as a candidate pharmacodynamic endpoint and outline a path toward its validation. Full article

The discovery of ferroptosis and cuproptosis has significantly expanded the landscape of programmed cell death. Artesunate (ART), a semisynthetic derivative of artemisinin, exhibits pleiotropic pharmacological activities beyond its canonical antimalarial role, including anticancer and neuroprotective effects. However, a comprehensive review systematically integrating ART’s roles in modulating both ferroptosis and cuproptosis remains lacking. This review bridges this gap by synthesizing recent advances. The distinct core mechanisms of ferroptosis and cuproptosis are first outlined. Extensive evidence is then summarized regarding ART-induced ferroptosis in cancers, primarily through disrupting iron homeostasis (e.g., stabilizing transferrin receptor (TFRC), promoting ferritinophagy) and impairing antioxidant defenses (e.g., suppressing the System Xc⁻/ glutathione peroxidase 4 (GPX4) axis, targeting peroxiredoxins). In contrast, the anti-cuproptotic effect of ART is currently restricted to Parkinson’s disease (PD) models, mediated by the upregulation of astrocytic metallothionein 2A (MT2A) to chelate excess copper—the only validated cuproptosis-related mechanism of ART to date. The crosstalk between ferroptosis and cuproptosis at shared metabolic nodes, including glutathione depletion, mitochondrial dysfunction, and reactive oxygen species (ROS) amplification, is further delineated as a hypothesis-generating framework. This interplay suggests a theoretical potential for ART—when combined with functional nano-materials—to synchronously engage both death pathways, though direct experimental validation of such dual-pathway synergy for ART as a single agent remains lacking. Finally, translational prospects of ART in cancer therapy, neurodegenerative diseases, and hepatic fibrosis are discussed, together with current challenges and future directions. ART acts as a context-dependent modulator: pro-ferroptotic activity is evident across multiple disease models, whereas anti-cuproptotic activity is currently limited to PD and requires further validation. Systematic characterization of ART’s context-specific effects suggests a preclinical rationale for the future design of ART-based combination strategies targeting metal-dependent cell death, pending further validation. Full article

Dihydroquercetin (DHQ), a powerful antioxidant and regulator of cellular metabolism, was proposed for therapy of neurodegenerative disorders. Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS) are serious neurodegenerative disorders with oxidative stress as an overlapping feature and unmet therapeutic needs. To date, few studies have explored the efficacy of DHQ in animal models of genetically driven neurodegeneration. Here, APPswe/PS1dE9 (APP/PS1) mice and their wild-type (WT) littermates were orally administered DHQ (0.6 mg/kg/day) for four months, starting at eight months of age. At the age of 12 months, behavioral evaluation was performed, followed by brain staining with Congo red for amyloid plaque scoring and immunohistochemical analysis of GFAP-positive cells for the assessment of astrogliosis. Malondialdehyde (MDA) levels in the prefrontal cortex were studied as a marker of oxidative stress. Second, two-month-old FUS[1-359]-Tg mice, which recapitulate the hallmarks of ALS, received DHQ for 1.5 months and were investigated for general physiological parameters, the onset of paralysis, motor functions, and density of motor neurons in the spinal cord. DHQ-treated APPswe/PS1dE9 mutants displayed a decrease in amyloid plaque density of small size (≤100 μm) in the cortex and thalamus, had normalized MDA levels, improved conditioned taste aversion and Y-maze learning, and ameliorated anxiety measures, whereas their hippocampus-dependent step-down and pellet displacement performance remained impaired. In the second study, DHQ-treated FUS[1-359]-Tg mice showed rescued density of spinal cord neurons, normalized liquid and diet intake, and improved coat state, while the onset of paralysis and motor scores were not significantly ameliorated. Thus, chronic administration of low doses of DHQ exerted neuroprotective effects in both AD and ALS genetic models, which partially translated to reduced manifestations of these diseases. Full article

CA, a major bioactive component of cinnamon essential oil, possesses broad-spectrum antibacterial, anti-inflammatory, and antioxidant activities and is widely recognized as a safe food additive. In the context of exploring natural plant extracts for the prevention and alleviation of bovine mastitis, it is noteworthy that research and clinical reports on the use of cinnamon essential oil for bovine mastitis are relatively limited. In this study, S. aureus isolates recovered from subclinical bovine mastitis were used to establish a mastitis infection model, and the antioxidant and anti-inflammatory effects of CA were preliminarily investigated in both mouse mastitis models and mammary epithelial cells (MAC-T). Studies have demonstrated that in a mouse model of mastitis, CA reduces inflammatory cell infiltration, decreases myeloperoxidase (MPO) activity, and inhibits S. aureus colonization in mammary tissue. CA alleviates oxidative stress by lowering malondialdehyde (MDA) levels, enhancing superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, and activating the Nrf2/HO-1/xCT antioxidant pathway. In addition, CA suppresses the activation of the TLR4/NF-κB signalling pathway and modulates the expression of Bax and Bcl-2, accompanied by reduced levels of pro-inflammatory cytokines, including tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), ultimately ameliorating mastitis in mice. In the MAC-T cell infection model, CA significantly inhibited S. aureus adhesion and invasion and decreased the production of pro-inflammatory cytokines and mediators. CA also activated the Nrf2/HO-1/xCT antioxidant pathway, which led to decreased intracellular reactive oxygen species (ROS), concurrently inhibited the TLR4/NF-κB pathway, and downregulated apoptotic protein expression, ultimately attenuating inflammation in MAC-T cells. Collectively, these findings demonstrate that CA exerts protective effects against inflammation and oxidative damage in both mammary tissues and epithelial cells infected with S. aureus. Thus, this study provides a theoretical and practical basis for further exploring CA as a candidate therapy for bovine mastitis. Full article

Objectives: This study aims to compare the effects of three interventions, namely hyperbaric oxygen (HBO) therapy, HBO combined with lycopene (LYC) supplementation, and natural recovery, on oxidative stress and inflammatory responses following high-intensity exercise. The goal is to provide a theoretical foundation and methodological reference for strategies that help reduce fatigue after intense physical activity. Methods: Collegiate badminton players (n = 45) were randomly assigned to control, HBO, and HBO+LYC groups. Each group completed a 4-week intervention in accordance with its assigned protocol. The levels of oxidative stress, inflammation-related markers, and exercise-induced fatigue indicators were assessed before and after the intervention. Changes in these markers following high-intensity exercise were analyzed using repeated-measures ANOVA to evaluate the effects of HBO and HBO+LYC. Results: Following the intervention, the control group showed significant increases in malondialdehyde (MDA), interleukin-6 (IL-6), tumor necrosis factor (TNF), C-reactive protein (CRP), creatine kinase (CK), blood urea (BU), and heart rate (HR), along with a significant decrease in testosterone (T) (all p < 0.05). Compared with the control group, both intervention groups had significantly lower MDA, IL-6, TNF, CRP, CK, BU, and HR and higher superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (T-AOC) (all p < 0.05). Compared with the HBO group, the HBO+LYC group showed significantly higher CAT and lower IL-6 and CK levels (all p < 0.05). Conclusions: Both HBO alone and HBO+LYC effectively reduced oxidative stress, inflammation, and exercise-induced fatigue, as evidenced by decreased MDA, IL-6, TNF, CRP, CK, BU, and HR, along with increased SOD and CAT, T-AOC, and T. Moreover, HBO+LYC demonstrated superior efficacy over HBO alone for selected outcomes, particularly by further enhancing glutathione peroxidase 3 activity. These findings suggest that HBO, especially when combined with LYC, may be an effective strategy to attenuate oxidative stress and inflammation and promote recovery following high-intensity exercise. Full article

Introduction: Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disorder involving ROS and ferroptosis. MXene, a 2D material, functions as both a drug carrier and ROS scavenger. Butylphthalide (NBP), a neuroprotective agent, suffers from poor aqueous solubility and bioavailability. This study synthesized Ti₂C@BSA-NBP, a novel MXene nanocomposite, to enhance NBP delivery and therapeutic efficacy for AD. Materials and Methods: Ti₂C@BSA-NBP was synthesized via self-assembly and amidation reaction, and characterized by multiple techniques. In vitro, ROS-scavenging capacity, mitochondrial function, and ferroptosis markers were assessed in H₂O₂-injured cells. In vivo efficacy was evaluated in an AD mouse model via behavioral, histopathological, and biochemical analyses. Results: The nanocomposite exhibited robust ROS-scavenging activity in vitro, significantly attenuating ROS, restoring mitochondrial function, and reversing ferroptosis markers. In vivo, Ti₂C@BSA-NBP ameliorated learning/memory deficits, partially repaired neuronal morphology, and suppressed neuroinflammation. Mechanistically, it downregulated ACSL4 and Aβ overexpression while restoring GPX4 inhibition. Discussion: Ti₂C@BSA-NBP exerts synergistic neuroprotection through MXene-mediated ROS clearance and NBP-mediated multi-target regulation, counteracting oxidative stress, ferroptosis, and neuroinflammation. Conclusions: Ti₂C@BSA-NBP is a promising multifunctional nanoplatform integrating antioxidant activity, enhanced drug delivery, and ferroptosis modulation for AD therapy. Full article

Background: Chronic autoimmune thyroiditis (CAT) is characterized by persistent autoimmune activity and increased oxidative stress, which may contribute to thyroid follicular injury and disease progression. Photobiomodulation (PBM) has shown potential beneficial effects on thyroid function and autoimmunity; however, its independent effect on systemic antioxidant status, particularly serum glutathione (GSH), has not been established. This study aimed to evaluate the effect of thyroid-directed PBM on serum GSH concentrations and thyroid-related outcomes in treatment-naïve euthyroid women with CAT. Methods: This prospective, non-randomized, open-label, parallel-group comparative interventional study included 50 treatment-naïve euthyroid women with CAT. Participants were allocated to receive either thyroid-directed transdermal PBM (n = 25) or selenium plus vitamin D supplementation (n = 25). The primary outcome was the change in serum GSH concentration. Secondary outcomes included changes in thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), anti-thyroid peroxidase antibodies (anti-TPO), anti-thyroglobulin antibodies (anti-Tg), thyroid volume, and anthropometric parameters. Assessments were performed at baseline (T0), after the intervention period (T1), and three months after intervention completion (T2). Results: A significant time × group interaction was observed for serum GSH concentrations (F = 19.101, p < 0.0001). Significant interactions were also observed for anti-TPO (F = 7.513, p = 0.001), anti-Tg (F = 7.389, p = 0.002), and thyroid volume (F = 13.081, p < 0.0001). In the PBM group, GSH increased from baseline to T1 and remained higher at T2, while TSH, anti-TPO, anti-Tg, and thyroid volume decreased, and FT3 and FT4 increased. No significant longitudinal changes in GSH or thyroid autoantibodies were observed in the supplementation group. No participant in the PBM group required levothyroxine (LT4) initiation during follow-up, whereas 24% of participants in the supplementation group initiated LT4 therapy at T1, with some requiring dose escalation by T2. Conclusions: Thyroid-directed PBM was associated with improved systemic GSH status and favorable changes in thyroid autoimmunity, thyroid function parameters, and thyroid volume compared with selenium plus vitamin D supplementation in treatment-naïve euthyroid women with CAT. These findings suggest that modulation of oxidative stress may represent one potential biological pathway underlying the observed effects of PBM. Larger randomized controlled studies with longer follow-up are required to confirm these findings and define the clinical role of PBM in autoimmune thyroid disease. Full article