Search Results (192)

Background/Objectives: To date there is a lack of an integrative review literature on redox homeostasis, oxidative stress and the influence on metabolic pathways and plasticity in uveal melanoma (UM), since most literature findings are from cutaneous melanoma (CM), a genetically and behaviorally distinct cancer. Furthermore, UM metabolic pathway comparison to other cancers could provide more insight into metastatic UM, a difficult-to-treat malignancy. Methods: A wide-ranging multi-step literature search of PubMed and Web of Science for redox balance, oxidative stress, antioxidants and metabolic plasticity in UM, with expanded search terms for connections with other cancers. Results: UM cells maintain redox homeostasis via several redox loops: glutathione, thioredoxin, peroxiredoxins, peroxisomal catalase and the mitochondrial antioxidative network. NADPH plays a key role in regenerating UM antioxidative capabilities. Key redox signaling pathways are the subject of ongoing research in UM: NRF2 signaling, AMPK, mTOR, MAPK, FoxO. These pathways are less studied versus CM and present behavior differences in UM. PON2, studied in CM, represents a literature gap in UM. Inside the tumoral microenvironment, UM presents high metabolic plasticity and easy switching from glycolysis to oxidative phosphorylation (OXPHOS). Thus, UM eschews the classic Warburg effect loop and instead presents high oxidative phosphorylation (OXPHOS) gene expression, which generates additional lactate, which in turn produces cascade reprogramming in the metabolic pathways and lactate metabolism particularities associated in experimental studies with immune-escape phenomena. Uveal melanoma’s OXPHOS capabilities confer survival advantages and subdivide tumoral populations into OXPHOS-high and OXPHOS-low variants. Glycolysis/OXPHOS metabolic plasticity is an ongoing research field in other cancers with common and different elements vs. UM: cutaneous melanoma, small cell lung carcinoma, pancreatic cancer, breast cancer, acute myeloid leukemia, prostate cancer, renal cell carcinoma and glioblastoma. Uveal melanoma cells are susceptible to deleterious effects of prooxidants, a metabolic vulnerability which helps to create genetic pleomorphism, selecting higher proliferation and dissemination variants. Conclusions: Uveal melanoma is an oncogenic mutation and mitochondrial metabolism-driven malignancy, with metabolic connections to other malignancies. Emerging understanding of redox homeostasis, redox pathway signaling, mitochondrial oxidative and oncogenic metabolism could lead to better understanding of therapeutic response and new therapeutic targets. This review novelly integrates the general and CM redox literature with the UM literature, painting a complex redox signaling and metabolic plasticity picture of UM. Full article

Background/Objectives: Oxidative and electrophilic stress-response pathways contribute to cellular resilience across various chronic diseases, including neurodegenerative, hepatic, and metabolic disorders. Pharmacological activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is a validated strategy to counteract oxidative damage, as evidenced by the clinical approval of dimethyl fumarate (DMF) and monomethyl fumarate (MMF) for relapsing forms of multiple sclerosis; both electrophilic compounds activate Nrf2 via covalent Keap1 (Kelch-like ECH-associated protein 1) modification. Cynara scolymus L. contains structurally related electrophilic metabolites; however, their contribution to Nrf2-associated signaling remains undefined. This study aimed to identify and characterize the constituents responsible for Nrf2-inducing activity and benchmark their potency against DMF and MMF. Methods: Bioactivity-guided fractionation combining Soxhlet extraction, Nrf2/ARE luciferase reporter screening, semi-preparative HPLC, and spectroscopic identification was employed. Functional validation included extracellular thiol quantification, H₂O₂ cytoprotection assays, and Western blot analysis of heme oxygenase-1 (HO-1). Results: The dichloromethane extract exhibited the highest Nrf2-inducing activity (54.4-fold). Fractionation yielded five guaianolide sesquiterpene lactones (1–5), four of which were active. The α-methylene-γ-lactone moiety was essential for activity. Aguerin B (3) exhibited the highest activity (39.14 ± 11.13-fold), while TBA analysis identified cynaropicrin (2) as the dominant extract-level contributor (62.9% of total activity). Notably, aguerin B (3) and cynaropicrin (2) induced greater reporter activity than DMF and MMF. Downstream pathway induction was confirmed by concentration- and time-dependent HO-1 upregulation, elevated extracellular glutathione and cysteinylglycine levels, and significant protection against H₂O₂-induced cytotoxicity without intrinsic toxicity. Conclusions: Guaianolide sesquiterpene lactones are the primary mediators of Nrf2-associated antioxidant signaling in C. scolymus. Cynaropicrin (2) exhibited stronger in vitro ARE-reporter induction than fumarates, supporting its relevance for further pharmacological investigation. Full article

Vitiligo is a multifactorial depigmentation disorder involving complex interactions among oxidative stress, immune dysregulation, inflammatory signaling, and programmed cell death pathways, which act as a central driver of melanocyte dysfunction and loss, interacting with immune-mediated cytotoxicity and intrinsic cellular susceptibility. Excessive reactive oxygen species (ROS) disrupt mitochondrial integrity, impair redox homeostasis, suppress microphthalmia-associated transcription factor (MITF)-dependent melanogenesis, and induce melanocyte apoptosis. Concomitant dysfunction of the nuclear factor erythroid 2-related factor 2 (NRF2)/antioxidant response element (ARE) axis further exacerbates oxidative injury by limiting endogenous antioxidant capacity. Current therapeutic approaches, including corticosteroids, phototherapy, and targeted immunomodulators, achieve partial repigmentation but do not adequately resolve melanocyte-intrinsic redox imbalance. This structured narrative review comprehensively integrates mechanistic and translational evidence to define phytocompounds as redox-active, multi-target modulators in vitiligo. Plant-derived polyphenols, flavonoids, terpenoids, and related metabolites are shown to attenuate ROS accumulation, preserve mitochondrial function, activate NRF2-dependent antioxidant signaling, and restore MITF-mediated expression of tyrosinase and associated melanogenic enzymes. Furthermore, coordinated modulation of MAPK, PI3K/Akt, and JAK/STAT pathways highlights their capacity to regulate immune–oxidative crosstalk and promote melanocyte survival. Despite promising preclinical and emerging clinical evidence of repigmentation efficacy, translational progress remains limited by poor phytochemical standardization, insufficient transcriptional and proteomic validation, suboptimal stability and dermal bioavailability, and a lack of rigorously designed clinical trials. Collectively, this review provides a mechanistic framework linking redox dysregulation to melanocyte failure and positions phytocompounds as rational candidates for adjunctive or stand-alone antioxidant-based therapies, while defining critical priorities for clinical translation. Full article

Polybrominated diphenyl ethers (PBDEs), widely used as brominated flame retardants, are known to exert persistent adverse effects on the immune systems of humans and other organisms. Previous studies have demonstrated that 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), a prevalent congener, induces apoptosis, impairs phagocytic function, and triggers aberrant immune-inflammatory reactions in RAW264.7 macrophages via the induction of elevated intracellular reactive oxygen species (ROS). However, the underlying regulatory mechanism remains unclear. The nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway is a key cellular defense system against oxidative stress. In this study, we investigated the role of the Nrf2/ARE pathway in BDE-47-induced macrophage immunotoxicity. Network toxicology analysis identified Nrf2 as a hub gene within the BDE-47-associated immunotoxicity network. Molecular docking and molecular dynamics simulations suggested a potential interaction between BDE-47 and the Keap1-Nrf2 complex, with moderate binding affinity. Experimental studies in RAW264.7 cells showed that BDE-47 exposure activated the Nrf2/ARE pathway, as evidenced by Nrf2 nuclear translocation and the differential upregulation of downstream genes (GCLC, GCLM, HO-1, NQO1, SOD1, and CAT). Importantly, Nrf2 knockdown via lentiviral shRNA or pharmacological inhibition with brusatol significantly exacerbated BDE-47-induced apoptosis and immune dysfunction, including enhanced pro-inflammatory cytokine production and impaired phagocytosis. These results demonstrate that Nrf2/ARE pathway activation represents an adaptive antioxidant response and contributes to limiting BDE-47-induced cytotoxicity and immune impairment in macrophages. Full article

Against the backdrop of the full implementation of “antibiotic ban” and “zinc restriction” policies in livestock and poultry breeding, and the growing consumer demand for safe livestock and poultry products, the development of natural and efficient green feed additives has become crucial for the sustainable development of the animal husbandry industry. Curcumin, a natural polyphenolic compound extracted from the rhizome of Curcuma longa L., has attracted extensive attention in poultry production due to its various biological activities and safety. This paper thoroughly reviews the chemical structure and physicochemical properties of curcumin, and elaborates on its core molecular mechanisms of action, which mainly involve the regulation of nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE), nuclear factor-κB (NF-κB), peroxisome proliferator-activated receptor γ (PPAR-γ), and mitogen-activated protein kinase (MAPK) pathways to exert antioxidant, anti-inflammatory, antibacterial, immunomodulatory and lipid metabolism regulatory effects. It further clarifies the practical application value of curcumin in major poultry species including broilers, laying hens, ducks and quails, showing that curcumin can significantly improve poultry production performance, optimize meat and egg quality, protect intestinal health, and enhance the ability of poultry to resist stress and diseases. Meanwhile, the review notes curcumin’s current application limitations (low bioavailability, poor stability, unclear standardized dosage, and high industrialization cost) and proposes targeted future research directions to address these issues. In conclusion, curcumin is a promising green feed additive alternative to antibiotics, and its large-scale and standardized application in poultry production will effectively promote the green, healthy and sustainable development of the poultry industry. Full article

The nuclear factor erythroid 2–related factor 2 (NRF2) is a master transcription factor that orchestrates cellular defense against oxidative and electrophilic stress. Dysregulation of the KEAP1–NRF2–ARE pathway has been implicated in several dermatological disorders, including vitiligo, psoriasis, atopic dermatitis, photoaging, and radiation dermatitis. This review summarizes recent advances in the understanding of NRF2 activation mechanisms and highlights pharmacological and natural compounds with potential dermatological applications. A comprehensive analysis of natural, semisynthetic, and synthetic NRF2 modulators is provided, describing their chemical structures, synthetic approaches, mechanisms of action, preclinical and clinical evidence, and therapeutic relevance for skin disorders. Multiple classes of NRF2 activators, including isothiocyanates such as sulforaphane, triterpenoids such as omaveloxolone, flavonoids including baicalein and apigenin, alkaloids such as berberine, glycosides like afzelin and paeoniflorin, stilbenoids such as tapinarof, and α,β-unsaturated fumaric acid esters such as dimethyl fumarate, have demonstrated antioxidant, anti-inflammatory, and cytoprotective effects in keratinocytes and melanocytes. Some of these agents, particularly dimethyl fumarate and tapinarof, have advanced to clinical development or commercialization, whereas others remain at the preclinical stage but show encouraging results in animal models and cell culture systems. Overall, pharmacological activation of NRF2 represents a promising therapeutic strategy to counteract oxidative stress–driven skin damage and inflammation; however, continued translational and clinical research is required to optimize formulations, dosing regimens, and safety profiles for integration into dermatological practice. Full article

Sulforaphane (SFN), an aliphatic isothiocyanate derived from cruciferous vegetables such as broccoli, has emerged as a chemopreventive dietary agent. SFN exerts multifaceted anticancer effects through the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)–antioxidant response element (ARE) pathways, inhibition of histone deacetylases (HDACs) and hypoxia-inducible factor-1α (HIF-1α), and regulation of apoptosis and autophagy. Epidemiological studies have consistently associated cruciferous vegetable intake with reduced cancer risk, while mechanistic research has elucidated the capacity of SFN to modulate redox balance, detoxification pathways, and epigenetic processes. Recent clinical trials have further demonstrated its potential to reduce carcinogenic biomarker levels and support metabolic detoxification. This review integrates evidence from epidemiological observations, molecular mechanisms, and clinical studies to provide a comprehensive understanding of the role of SFN in cancer prevention and therapy. Finally, translational challenges, including limited bioavailability, dose optimization, and standardization of broccoli-derived preparations, are discussed as critical factors for successfully translating SFN therapies from bench to bedside. Full article

A new category of polyphenolic compounds, like flavonoids, phenolic acids, phenylpropanoids, terpenoids, and others, referred to as food nutrients, may counteract the harmful effects of micro- and nanoplastics (MNPs) by enhancing cellular stress resilience response and overall human health. These compounds found in functional food help mitigate the cellular damage, inflammation, and oxidative stress caused by MNP exposure, which can contribute to pathological conditions, including diabetes. Importantly, specific food nutrients are able to activate, at the minimum dose, the nuclear factor erythroid-derived 2-like 2 (Nrf2) to prevent or block MNP-induced damage. The Nfe2l2 gene encodes the Nrf2 transcription factor, acting as a master regulator of redox homeostasis by inducing antioxidant response element (ARE)-driven resilience genes, which in turn, promote the expression of detoxification enzymes like heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase 1 (NQO1), and glutathione S-transferase (GST) to scavenge reactive oxygen species (ROS) and shield cells from environmental damage and toxicity. Deregulation of the Nfe2l2 gene due to the accumulation of MNP pollutants may exacerbate the inflammatory conditions associated with diabetes and its chronic complications by rendering cells more sensitive to oxidative stress, apoptosis, and pyroptosis. Furthermore, epigenetic modifications influence gene regulation; chromatin remodeling directly impacts DNA accessibility, allowing or limiting transcription factor access to regulate gene expression. This mechanism may also play a pivotal role in the progression of oxidative stress-related diseases, as it modulates the Nrf2 pathway and the expression levels of its target genes. In contrast to the current literature, which has only addressed the pathological mechanisms induced by MNPs, this research explores, for the first time, how food nutrients interacting with the Nfe2l2 gene can combat or reverse the toxic effects of MNPs in cells, tissues, and organs. The goal is to improve health by attenuating MNP toxicity, which is influenced by individual genetic variations and cellular stress resilience. Full article

Background/Objectives: Females are generally more resistant to ischemia-related ferroptosis than males, due to differences in iron metabolism, antioxidant pathways, and sex hormone-mediated regulation of ferroptosis suppressors. This has not been systematically studied in a human donor liver model. To investigate the effect of sex on ferroptosis and oxidative stress pathways in non-utilized donor livers (NDLs), we assessed patterns of gene expression in NDLs under ex vivo normothermic machine perfusion (NMP). Methods: We utilized the PROTECT dual-circuit ex vivo NMP system to assess three male and two female NDLs undergoing 6 h NMP. Perfusate and tissue samples were collected at baseline and 6 h of NMP. Malondialdehyde (MDA) levels were quantified as biochemical markers of iron overload and lipid peroxidation, respectively. Ferroptosis-related gene expression was assessed using molecular assays. Comparisons between male and female NDLs were used to determine the influence of sex on ferroptosis and oxidative injury during NMP. Results: NMP was successfully performed on NDLs (n = 5) from three male (56.3 ± 5.7 years) and two female donors (46.5 ± 0.7 years, p = 0.15). The fold-change in the oxidative stress marker MDA was comparable between female (1.2 ± 0.6) and male (1.0 ± 0.4) NDLs after 6 h NMP (p = 0.76). All livers showed upregulation of ferroptosis-related genes (Hypoxia-inducible factor 1 alpha, Iron Responsive Binding Elements 2, Ribosomal Protein L8, Ferritin Heavy Chain 1, Acyl-CoA synthetase family member 2, ATP synthase membrane subunit c locus 3, Heme-oxygenase 1, NAD(P)H Quinone Dehydrogenase 1, Tetratricopeptide Repeat Domain 35, Nuclear Factor Erythroid 2 Related Factor 2). ACSF2 expression was significantly higher in female NDLs compared with males undergoing 6 h NMP (3.6 ± 3.0 vs. 1.0 ± 0.7-fold change, p = 0.04). There were no sex-based significant differences observed in the expression of other ferroptosis-related genes (HIF-1α, IREB2, RPL8, FTH-1, ATP5G3, HO-1, NQO1, TTC35, and NRF2) between male and female NDLs. No gene reached statistical significance after false-discovery-rate (FDR) correction. Conclusions: Normothermic machine perfusion of NDLs was feasible, and no sex-related differences were observed in MDA levels or most ferroptosis-related gene expression after 6 h. Although ACSF2 showed higher expression in female livers, this was not significant after multiple testing correction, highlighting the need for larger studies to explore sex-dependent ferroptosis signaling during liver preservation. Full article

Quercetin (Q), a bioactive flavonoid, exerts potent antioxidant and redox-modulating effects by activating the nuclear factor erythroid 2-related factor 2/antioxidant response Element (Nrf2/ARE) pathway and upregulating endogenous antioxidant defenses, including enzymatic antioxidants such as superoxide dismutase (SOD) and catalase (CAT), as well as non-enzymatic glutathione (GSH) and lipid peroxidation (MDA). Gemcitabine (Gem), a widely used antimetabolite chemotherapeutic, often shows limited efficacy under hypoxic and oxidative stress conditions driven by hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF)-mediated angiogenesis. This study investigated the redox-mediated synergistic effects of Q and Gem in MDA-MB-231 human breast cancer cells. Combination treatment significantly reduced cell viability beyond the expected Bliss value, indicating a synergistic interaction and enhanced apoptosis compared with single-agent treatments. Increased reactive oxygen species (ROS) production was accompanied by depletion of GSH and accumulation of MDA, establishing a pro-apoptotic oxidative stress environment. Q alone enhanced SOD and CAT activities, whereas the combination induced exhaustion of antioxidant defenses under oxidative load, reflecting a redox-adaptive response. Molecular analyses revealed downregulation of HIF-1α and VEGF, alongside upregulation of Bax and Caspase-3, confirming suppression of hypoxia-driven survival and activation of the intrinsic apoptotic pathway. Transcriptomic and enrichment analyses further identified modulation of oxidative stress- and apoptosis-related pathways, including phosphoinositide-3-kinase–protein kinase B/Akt (PI3K/Akt), HIF-1 and VEGF signaling. Collectively, these results indicate that Q potentiates Gem cytotoxicity via redox modulation, promoting controlled ROS elevation and apoptosis while suppressing hypoxia-induced survival mechanisms, highlighting the therapeutic potential of redox-based combination strategies against chemoresistant breast cancer. Full article

Essential oils (EOs) are complex volatile mixtures that exhibit antioxidant activity through both chemical and biological pathways. Phenolic constituents act as efficient chain-breaking radical-trapping antioxidants, whereas some non-phenolic terpenes operate through distinct mechanisms. Notably, γ-terpinene functions via a “radical export” pathway, generating hydroperoxyl radicals that intercept lipid peroxyl radicals and accelerate chain termination. Recent methodological advances, such as inhibited autoxidation kinetics, oxygen-consumption assays, and fluorescence-based lipid peroxidation probes, have enabled more quantitative evaluation of these activities. Beyond direct radical chemistry, EOs also regulate redox homeostasis by modulating signaling networks such as Nrf2/Keap1, thereby activating antioxidant response element–driven enzymatic defenses in cell and animal models. Phenolic constituents and electrophilic compounds bearing an α,β-unsaturated carbonyl structure may directly activate Nrf2 by modifying Keap1 cysteine residues, whereas non-phenolic terpenes likely depend on oxidative metabolism to form active electrophilic species. Despite broad evidence of antioxidant efficacy, molecular characterization of EO–protein interactions remains limited. This review integrates radical-chain dynamics with redox signaling biology to clarify the mechanistic basis of EO antioxidant activity and to provide a framework for future research. Full article

This review synthesizes research on nuclear factor erythroid 2-related factor 2 (Nrf2) in intestinal health across human, livestock, and mouse models. The Nrf2 signaling pathway serves as a master regulator of cellular antioxidant defenses and a key therapeutic target for intestinal inflammatory disorders, including ulcerative colitis and Crohn’s disease. The interplay between oxidative stress, Nrf2 signaling, and NF-κB inflammatory cascades represents a critical axis in the pathogenesis and resolution of intestinal inflammation. Under normal physiological conditions, Nrf2 remains sequestered in the cytoplasm by Kelch-like ECH-associated protein 1 (Keap1), which facilitates its ubiquitination and proteasomal degradation. However, during oxidative stress, reactive oxygen species (ROS) and electrophilic compounds modify critical cysteine residues on Keap1, disrupting the Keap1-Nrf2 interaction and enabling Nrf2 nuclear translocation. Once in the nucleus, Nrf2 binds to antioxidant response elements (ARE) in the promoter regions of genes encoding phase II detoxifying enzymes and antioxidant proteins, including heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutamate-cysteine ligase. This comprehensive review synthesizes current evidence demonstrating that activation of Nrf2 signaling confers protection against intestinal inflammation through multiple interconnected mechanisms: suppression of NF-κB-mediated pro-inflammatory cascades, enhancement of cellular antioxidant capacity, restoration of intestinal barrier integrity, modulation of immune cell function, and favorable alteration of gut microbiota composition. We systematically examine a diverse array of therapeutic agents targeting Nrf2 signaling, including bioactive peptides, natural polyphenols, flavonoids, terpenoids, alkaloids, polysaccharides, probiotics, and synthetic compounds. The mechanistic insights and therapeutic evidence presented underscore the translational potential of Nrf2 pathway modulation as a multi-targeted strategy for managing intestinal inflammatory conditions and restoring mucosal homeostasis. Full article

Astrocytes play a key role in maintaining redox balance and supporting neuronal survival within the central nervous system (CNS). Their antioxidant machinery, primarily involving the Nrf2–ARE (nuclear factor erythroid 2-related factor 2–antioxidant response element) pathway, glutathione (GSH) metabolism, and mitochondrial function, enables the removal of reactive oxygen and nitrogen species (ROS and RNS) and supports neuronal resistance to oxidative stress. Effective communication between neurons and astrocytes coordinates metabolic and antioxidative responses via glutamate-, nitric oxide-, and calcium-dependent signalling. Disruption of this crosstalk during traumatic injury, ischemia, or neurodegenerative disease causes redox imbalance, neuroinflammation, and excitotoxicity, which contribute to progressive neurodegeneration. Astrocytic Nrf2 activation reduces oxidative damage and inflammation, while its suppression encourages a neurotoxic glial phenotype. Current evidence emphasizes various therapeutic strategies targeting astrocytic redox mechanisms, including small-molecule Nrf2 activators, GSH precursors, mitochondria-targeted antioxidants (MTAs), and RNA- and gene-based approaches. These interventions boost the antioxidant ability of astrocytes, influence reactive cell phenotypes, and support neuronal recovery in preclinical models. Although there are still challenges in delivery and safety, restoring neuron–glia redox signalling offers a promising strategy for neuroprotective treatments aimed at reducing oxidative stress-related CNS injury and disease progression. Full article

Polyphenol-rich fruits represent promising natural candidates for mitigating oxidative stress. We determined in dose–response manner the intracellular antioxidant activities of P. cerasus (tart cherry) extract in HepG2 cells using three different cellular assays targeting specific mechanisms of action: (1) the AOP1 assay, to assess intracellular ROS scavenging activity; (2) the CAA assay, to estimate ROS scavenging activity at the cell membrane; and (3), the HepG2-ARE-luc assay, to evaluate Antioxidant Response Element (ARE) pathway modulation. Tart cherry extract exhibited a high and concentration-dependent intracellular ROS scavenging activity with the AOP1 assay (EC₅₀ of 72.02 µg/mL), whereas antioxidant efficacy measured via the CAA assay was much lower (EC₅₀ of 6.975 mg/mL). Notably, P. cerasus extract did not activate the ARE-driven luciferase gene expression. Instead, the extract induced a clear dose-dependent repression of ARE-driven transcriptional activity, with a reduction in luciferase gene expression ranging from 20 to 70% across the sample tested concentrations (0.38–98 µg/mL). These findings suggest that, at concentrations where it functions as a potent intracellular ROS scavenger, P. cerasus extract exerts a negative regulation of the ARE pathway. Further investigations are warranted to elucidate the compounds underlying these effects. Full article

Aging contributes to neurodegeneration, predominantly characterized by increased oxidative stress, which leads to neurodegenerative changes and cognitive decline. This cognitive impairment is often associated with neuroinflammation, oxidative stress, and neuronal damage. Exercise is widely recognized for its capacity to elevate levels of irisin, a hormone derived from the cleavage of fibronectin type III domain-containing protein 5 (FNDC5). FNDC5/irisin acts as a myokine that mediates numerous beneficial effects of physical activity on metabolic health. It has also been recognized for its neuroprotective roles, suggesting its potential to mitigate neurodegenerative processes by promoting neuronal survival, reducing oxidative stress, and enhancing synaptic plasticity. However, the specific impact of exercise on the FNDC5/irisin pathway and antioxidant mechanisms in the aged brain remains insufficiently explored. In this study, we aimed to validate the neuroprotective role of exercise-induced FNDC5/irisin against aging-related oxidative stress, glial activation, neuronal damage, and cognitive impairment in 20-month-old mice. The exercise group underwent treadmill running for 60 min daily over an 8-week period. Our findings indicated that aging mice exhibited cognitive impairment, as evidenced by the Y-maze test; however, treadmill exercise effectively alleviated this impairment. Aged mice showed the activation of microglia and astrocytes in the hippocampus, which was notably reduced by exercise. Moreover, exercise improved the levels of calbindin and irisin, which were diminished due to aging. Our study demonstrated that aging led to a decrease in the antioxidant response element system and FNDC5/irisin pathway. However, exercise effectively activated Nrf2 and FNDC5/irisin expression, subsequently enhancing levels of SOD1, GSTO1/2, Sirt1, PGC-1α, BDNF, IGF-1, and IGF-2 in the hippocampus. The exercise-induced activation of Nrf2 signaling and FNDC5/irisin has emerged as a potent mechanism for alleviating oxidative stress and neuroinflammation associated with aging. In conclusion, our findings suggest that regular exercise has the potential to alleviate cognitive impairment through the activation of PGC-1α-FNDC5/irisin signaling, the Nrf2 ARE system, and neurotrophic factors in aged mice. Full article