Free Radical Biology and Medicine最新文献

{"title":"Evidence that the aryl hydrocarbon receptor orchestrates oxinflammatory responses and contributes to airborne particulate matter-induced skin aging","authors":"Frederick Hartung ,&nbsp;Jean Krutmann ,&nbsp;Thomas Haarmann-Stemmann","doi":"10.1016/j.freeradbiomed.2025.03.040","DOIUrl":"10.1016/j.freeradbiomed.2025.03.040","url":null,"abstract":"<div><div>Exposure to airborne particulate matter (PM) is a substantial threat to public health, contributing to respiratory, cardiovascular, and skin-related diseases. Population-based studies strongly indicate that chronic exposure to airborne PM, especially combustion-derived PM_2.5, accelerates skin aging and thus reduces the quality of life of those affected. There is increasing evidence that especially PM-bound polycyclic aromatic hydrocarbons (PAHs) critically contribute to the clinical manifestation of skin aging, i.e. the development of lentigines/pigment spots and coarse wrinkles. PAHs harm human skin primarily by activating the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor amongst others involved in orchestrating xenobiotic metabolism and immune responses. In this review, we summarize the available population-based data linking particulate air pollution exposure to skin aging. We explain in detail how PAH-rich PM induces the formation of oxidative stress, the release of pro-inflammatory mediators, the expression extracellular matrix degrading metalloproteases, and melanin synthesis, in an AHR-dependent manner, and how these events may culminate in the development of pigment spots and wrinkles, respectively. We also review the current data on the interaction of airborne PM with another factor of the skin aging exposome that exerts its deleterious effects in part through AHR-dependent signaling pathways, namely solar ultraviolet radiation.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 264-278"},"PeriodicalIF":7.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Iron overload exacerbates metabolic dysfunction-associated steatohepatitis via the microbiota-gut-liver axis through lipopolysaccharide-mediated Akr1b8 activation","authors":"Yu Han ,&nbsp;Yuhui Zhang ,&nbsp;Jianjun Chen ,&nbsp;Shouchuan Jiang ,&nbsp;Yi Zheng ,&nbsp;Yecheng Xu ,&nbsp;Yunqin Li ,&nbsp;Jingxia Kong ,&nbsp;Xin Yu ,&nbsp;Huahua Du","doi":"10.1016/j.freeradbiomed.2025.03.039","DOIUrl":"10.1016/j.freeradbiomed.2025.03.039","url":null,"abstract":"<div><div>Iron homeostatic is closely linked to the development of metabolic dysfunction-associated steatohepatitis (MASH). However, the underlying mechanisms remain poorly understood. HFE knockout (KO) mice were used to generate mild iron-overload models. MASH was induced by feeding mice a methionine- and choline-deficient (MCD) diet for 4 weeks. Iron overload significantly exacerbated the pathologies of MCD-induced MASH, including liver injury, hepatic lipid accumulation, inflammation, and fibrosis. Additionally, iron overload reshaped the composition of gut microbiota, and fecal microbiota transplantation assay proved that gut microbiota from iron-overload mice contributed to hepatic lipid accumulation in control mice. Furthermore, iron overload-induced dysbacteriosis altered the metabolite profiles, reducing short-chain fatty acid levels and increasing lipopolysaccharide (LPS) levels. Notably, elevated LPS levels upregulated the expression of aldo-keto reductase family 1 member B8 (Akr1b8), which accelerated lipid accumulation and inflammation in hepatocytes. Above results indicated that iron overload promoted MASH progression through the microbiota-gut-liver axis, mediated by LPS-induced activation of Akr1b8. These findings highlight the critical role of iron homeostasis and gut microbiota in MASH pathogenesis.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 196-208"},"PeriodicalIF":7.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to 'Sterile inflammation induces vasculopathy and chronic lung injury in murine sickle cell disease' [Free Radic. Biol. Med. 215 (2024) 112-126].","authors":"Kevin R Rarick, Keguo Li, Ru-Jeng Teng, Xigang Jing, Dustin P Martin, Hao Xu, Deron W Jones, Neil Hogg, Cheryl A Hillery, Guilherme Garcia, Billy W Day, Stephen Naylor, Kirkwood A Pritchard","doi":"10.1016/j.freeradbiomed.2025.03.028","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.03.028","url":null,"abstract":"","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imbalanced redox dynamics induce fibroblast senescence leading to impaired stem cell pools and skin aging","authors":"Meinhard Wlaschek ,&nbsp;Pallab Maity ,&nbsp;Albert Kallon Koroma ,&nbsp;Hartmut Geiger ,&nbsp;Karmveer Singh ,&nbsp;Karin Scharffetter-Kochanek","doi":"10.1016/j.freeradbiomed.2025.03.024","DOIUrl":"10.1016/j.freeradbiomed.2025.03.024","url":null,"abstract":"<div><div>Skin function depends on a meticulously regulated dynamic interaction of distinct skin compartments such as the epidermis and dermis. Adaptive responses at the molecular and cellular level are essential for these interactions – and if dysregulated – drive skin aging and other pathologies. After defining the role of redox homeodynamics in physiology and aging pathology, we focus on the redox distress-dependent aging of dermal fibroblasts including their progenitors. We here discuss the prime role of senescent fibroblasts in the control of their own endogenous niche and stem cell niches for epidermal stem cells, hair follicle stem cells, adipocyte precursors and muscle stem cells. We here review that redox imbalance induced reduction in Insulin-like Growth Factor-1 drives skin aging by the depletion of stem cell pools.</div><div>This IGF-1 reduction is mediated via the redox-sensitive transcription factor JunB and also by the redox-dependent changes in sphingolipid-metabolism, among others. In addition, we will discuss the changes in the extracellular matrix of the skin affecting cellular senescence and the skin integrity and function in aging. The aim is a deeper understanding of the two main redox-dependent hubs such as JunB-induced depletion of IGF-1, and the sphingolipid-mediated remodeling of the cell membrane with its impact on IGF-1, fibroblast heterogeneity, function, senescence and plasticity in skin aging.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 292-301"},"PeriodicalIF":7.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular oxidative stress and sirtuins mediate regulation of senescence and neuronal differentiation by withaferin A","authors":"Keshava Prasad ,&nbsp;Sunil C. Kaul ,&nbsp;Renu Wadhwa ,&nbsp;Kanive P. Guruprasad ,&nbsp;Kapaettu Satyamoorthy","doi":"10.1016/j.freeradbiomed.2025.03.038","DOIUrl":"10.1016/j.freeradbiomed.2025.03.038","url":null,"abstract":"<div><div>Withaferin A (WA) and Withanone (WN), the steroidal lactones are pharmacologically established for anticancer and chemopreventive effects in certain cancers. However, their effects on redox modulations, mechanisms stimulating senescence and neuronal differentiation in neuroblastoma cells are less understood. Here we examined the influence of WA on perturbations in the molecular architecture of growth, differentiation and senescence of human brain cancer cell SH SY5Y <em>in vitro</em> and test its efficacy in mouse tumor models. We found senescence induction amplified by WA as determined by a senescence-associated β-galactosidase assay. This led us to evaluate DNA damage which was enhanced as measured by phospho-γH2AX foci formation, directed by reactive oxygen species (ROS) production as determined by flow cytometry and confocal imaging. Furthermore, we assessed the influence of DNA damage on cell cycle arrest and DNA repair. Neurosphere formation assay was performed to demonstrate the stem cell inhibitory potential of WA. Subcutaneous xenograft of neuroblastoma cells in athymic Balb/c mice was performed followed by treatment with WA and tumor growth inhibition was established. <em>Withania somnifera</em> (WS) extract and WA induced alterations in ROS, triggering DNA damage and concomitantly regulated SIRTs expression leading to activation of senescence in SH SY5Y cells. Upon prolonged incubation, differentiation into neuronal lineages was confirmed by using differentiation markers such as neurofilament medium, nestin, MAP2 and synaptophysin as measured by immunofluorescence and flow cytometry. The results suggest a complex interplay between the induction of senescence and concurrent neuronal differentiation of SH SY5Y cells mediated by early alterations in SIRT1 and SIRT3. Thus, we report the senescence and differentiation potential of WS extracts and WA through ROS that are mediated via modulation of SIRT1, SIRT3 and mitochondria function.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 174-185"},"PeriodicalIF":7.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting mitophagy using isoliensinine as a therapeutic strategy for renal cell carcinoma treatment","authors":"Ming-Ju Wu ,&nbsp;Yu-Teng Chang ,&nbsp;Tzu-Yi Chuang ,&nbsp;Wang-Sheng Ko ,&nbsp;Chih-Chiang Lu ,&nbsp;Jeng-Jer Shieh","doi":"10.1016/j.freeradbiomed.2025.03.037","DOIUrl":"10.1016/j.freeradbiomed.2025.03.037","url":null,"abstract":"<div><div>Renal cell carcinoma (RCC) is a formidable and lethal form of kidney cancer, necessitating the exploration of novel therapeutic options. Isoliensinine, an alkaloid derived from lotus seed embryos, has shown promising anti-cancer properties. However, its mechanistic actions and impact on mitochondrial dynamics remain poorly understood. This research has aimed to investigate the effects of isoliensinine on RCC, as well as its potential involvement in mitophagy and mitochondrial function. In vitro experiments utilizing RCC cell lines (786-O and ACHN) have demonstrated that isoliensinine treatment significantly reduced cell viability. Moreover, isoliensinine induced an increase in cellular and mitochondrial reactive oxygen species (ROS) levels, accompanied by reduced mitochondria membrane potential, indicating an influence on mitochondrial function. Furthermore, MitoTracker staining revealed distinct mitochondrial morphologies, with isoliensinine promoting mitochondrial fission, thus supporting its role in mitochondrial dynamics. Notably, isoliensinine led to a time-dependent upregulation of mitophagy-related proteins, indicative of mitophagy activation. Of particular interest, the addition of MitoTEMPO, a potent mitochondrial ROS scavenger, effectively reversed the isoliensinine-induced upregulation of mitophagy-related protein expression and mitochondrial ROS levels. These combined results provide novel insight into the impact of isoliensinine-induced mitophagy on mitochondrial dynamics in renal carcinoma cells. Overall, the findings from this study highlight isoliensinine as a promising candidate with significant potential for further investigation and eventual clinical application in RCC therapy. Moreover, the modulation of mitochondrial dynamics, mitophagy and ROS levels through the use of isoliensinine further adds to its appeal as a potential therapeutic agent.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 132-147"},"PeriodicalIF":7.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urinary total superoxide dismutase activity is low in rheumatoid patients, and its low levels are associated with higher DAS28 scores","authors":"Ahmet Kor ,&nbsp;Merve Yalçın ,&nbsp;Göktuğ Okyar ,&nbsp;Tahire Betül Kor ,&nbsp;İsmail Doğan ,&nbsp;Ebru Atalar ,&nbsp;Hatice Ecem Konak ,&nbsp;Pınar Akyüz Dağlı ,&nbsp;Dudu Çelik Tam ,&nbsp;Sema Işık ,&nbsp;Bünyamin Polat ,&nbsp;Salim Neşelioğlu ,&nbsp;Özcal Erel ,&nbsp;Şükran Erten","doi":"10.1016/j.freeradbiomed.2025.03.035","DOIUrl":"10.1016/j.freeradbiomed.2025.03.035","url":null,"abstract":"<div><h3>Aim</h3><div>Rheumatoid factor and anti-citrullinated peptide antibodies are generally used to diagnose rheumatoid arthritis (RA). However, these antibodies are negative in 15–20 % of RA cases. This study aimed to investigate new biomarkers that can be used in diagnosing RA and evaluating disease activity.</div></div><div><h3>Methods</h3><div>This study included 99 RA patients and 94 healthy volunteers. Modified Disease Activity Score28 (DAS28) erythrocyte sedimentation rate (ESR) was used for disease activity score. Thiol/disulfide molecules were measured using an automatic spectrophotometric method, and ischemia-modified albumin was measured using an albumin-cobalt binding test. A spectrophotometer calculated urinary and serum total superoxide dismutase (SOD) activities at 420 nm wavelength.</div></div><div><h3>Results</h3><div>In the RA group, serum IMA level was higher (unstandardized beta [B]: 5.552, Odds Ratio [OR]: 250.1, CI 95 %: 1.29–48219.1, p: .040), and urinary total SOD activities were significantly lower (B: 2.640 OR: .071, CI 95 %: .027–.192, p &lt; 0.0001) than in the control group. A cut-off value of 5.06 for urinary total SOD was found to have a sensitivity of 97.9 % and a specificity of 97 % in distinguishing RA patients from healthy controls (AUC [95 %Cl] = .986 [.967–1.000], p &lt; 0.001). Urinary total SOD activity was significantly lower in the RA subgroup with high disease activity compared to the groups with moderate disease activity (B: .954, OR: 2.596, CI 95 %: 1.104–6.103, p: .029) and low disease activity (B: 1.251, OR: 3.494, CI 95 %: 1.143–10.678, p: .028).</div></div><div><h3>Conclusion</h3><div>This study showed that urinary total SOD activity has high sensitivity and specificity in distinguishing RA patients from healthy controls and that RA patients with higher DAS28 ESR activity scores have lower urinary total SOD activity.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 77-85"},"PeriodicalIF":7.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143714263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Experiences of multiple psychosocial stressors and associations with oxidative stress biomarkers during pregnancy","authors":"Stephanie M. Eick ,&nbsp;Manuela L. Celia-Sanchez ,&nbsp;Tracey J. Woodruff ,&nbsp;Dana E. Goin ,&nbsp;Amy M. Padula ,&nbsp;Lara Cushing ,&nbsp;Kaegan Ortlund ,&nbsp;Erin DeMicco ,&nbsp;Ginger L. Milne ,&nbsp;Rachel Morello-Frosch","doi":"10.1016/j.freeradbiomed.2025.03.036","DOIUrl":"10.1016/j.freeradbiomed.2025.03.036","url":null,"abstract":"<div><h3>Background</h3><div>Oxidative stress is hypothesized to be one mechanism linking psychosocial stressor exposure to preterm birth and other adverse pregnancy outcomes. However, prior studies have focused solely on singular psychosocial stressors, which may not reflect real world exposures as pregnant women may experience multiple stressors simultaneously.</div></div><div><h3>Methods</h3><div>Participants included a subset of the Chemicals in Our Bodies cohort, a prospective birth cohort in San Francisco, California (N = 227). Self -reported psychosocial stressors were assessed via questionnaires administered during the second trimester that addressed financial strain, food insecurity, job strain, neighborhood quality, caregiving, stressful life events, unplanned pregnancy, and perceived community status. Oxidative stress biomarkers were measured during the second trimester of pregnancy and included 15-F_2t-IsoP, and its two major metabolites 2,3-dinor-5,6-dihydro-15-F_2t-IsoP, and 2,3-dinor-15-F_2t-IsoP, and PGF_2α. Linear regression models were used to examine associations between individual and pairwise combinations of psychosocial stressors in relation to each oxidative stress biomarker.</div></div><div><h3>Results</h3><div>15-F_2t-IsoP, 2,3-dinor-15-F_2t-IsoP, and 2,3-dinor-5,6-dihydro-15-F_2t-IsoP were elevated among participants reporting experiences of low perceived community status, job strain, poor neighborhood quality, food insecurity, and stressful life events (e.g., β = 0.36, 95 % CI = 0.00, 0.72 for food insecurity in association with 15-F_2t-IsoP). In models that included pairwise combinations of stressor exposures, nearly every combination was also associated with an increase in all oxidative stress biomarkers compared to those who experienced one or neither stressor. For example, stressful life events and poor neighborhood quality was associated with statistically significant increases in all biomarkers (e.g., β = 0.94, 95 % CI = 0.17, 1.71 for 2,3-dinor-5,6-dihydro-15-F_2t-IsoP).</div></div><div><h3>Conclusions</h3><div>Urinary oxidative stress biomarkers were elevated among pregnant women exposed to psychosocial stressors, and exposure to multiple stressors resulted in the strongest associations. These findings support oxidative stress as one potential biological pathway linking prenatal psychosocial stress to preterm birth and other adverse pregnancy outcomes.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 70-76"},"PeriodicalIF":7.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143714353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The clinical-grade CBP/ p300 inhibitor CCS1477 represses the global NRF2-dependent cytoprotective transcription program and re-sensitizes cancer cells to chemotherapeutic drugs","authors":"Ke Wang ,&nbsp;Liam Baird ,&nbsp;Masayuki Yamamoto","doi":"10.1016/j.freeradbiomed.2025.03.034","DOIUrl":"10.1016/j.freeradbiomed.2025.03.034","url":null,"abstract":"<div><div>Constitutive activation of NRF2 provides a selective advantage to malignant tumour clones through the hijacking of the NRF2-dependent cytoprotective transcriptional program, which allows the cancer cells to survive and thrive in the chemically stressful tumour niche, whilst also providing resistance to anti-cancer drugs due to the upregulation of xenobiotic metabolizing enzymes and drug efflux pumps. Through a small-molecule epigenetic screen carried out in <em>KEAP1</em> mutant lung cancer cells, in this study, we identified CCS1477 (Inobrodib) to be an inhibitor of the global NRF2-dependent transcription program. Mechanistically, CCS1477 is able to repress NRF2’s cytoprotective response through the inhibition of its obligate transcriptional activator partner CBP/p300. Importantly, in addition to repressing NRF2-dependent anti-oxidative stress and xenobiotic metabolizing enzyme gene expression, CCS1477 treatment is also able to reverse the chemoresistance phenotype and re-sensitize NRF2-activated tumour cells to anti-cancer drugs. Furthermore, in co-culture experiments of <em>KEAP1</em> mutant cancer cells with primary human T cells, CCS1477 treatment suppressed the acquisition of the T cell exhaustion transcriptional state, which should function to augment the anti-cancer immune response. Thus, CCS1477-mediated inhibition of CBP/p300 represents a novel therapeutic strategy with which to target the currently untreatable tumours with aberrant NRF2 activation.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 102-117"},"PeriodicalIF":7.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reductive stress and mitochondrial dysfunction: The hidden link in chronic disease","authors":"Joseph Mercola","doi":"10.1016/j.freeradbiomed.2025.03.029","DOIUrl":"10.1016/j.freeradbiomed.2025.03.029","url":null,"abstract":"<div><div>Conventional theories of oxidative stress have long focused on the deleterious consequences of excessive reactive oxygen species (ROS) formation. However, growing evidence reveals that an overload of reducing equivalents—termed <em>reductive stress</em>—may be equally pivotal in driving mitochondrial dysfunction and chronic disease. In this paradigm, abnormally high concentrations of NADH and NADPH create an electron “traffic jam” in the mitochondrial electron transport chain (ETC), leading to partial inhibition or reverse electron flow at upstream complexes. Paradoxically, this hyper-reduced environment promotes ROS generation by increasing electron leakage to molecular oxygen, thereby intensifying oxidative damage to lipids, proteins, and mitochondrial DNA.</div><div>This review explores the intertwined nature of reductive and oxidative stress, showing how a surplus of reducing equivalents can potentiate metabolic derangements in conditions such as type 2 diabetes, nonalcoholic fatty liver disease, and neurodegenerative disorders. The review discusses common drivers of reductive overload, including chronic hyperglycemia, high-fat diets, and specific dietary patterns—particularly those enriched in polyunsaturated omega-6 fatty acids—that inundate mitochondria with electron donors. The review also highlights emerging evidence that targeted assessment of redox biomarkers (e.g., lactate:pyruvate, β-hydroxybutyrate:acetoacetate ratios) can provide clinically relevant indicators of reductive stress.</div><div>Finally, the review examines how novel therapeutic strategies can address the underlying reductive imbalance, from rational nutrient modulation to pharmacologic interventions that restore NAD⁺ levels or optimize ETC flux. Recognizing reductive stress as a critical inflection point in mitochondrial pathophysiology underscores the need for a refined redox framework, one that moves beyond conventional oxidative paradigms to embrace the full spectrum of redox dysregulation in chronic degenerative disease.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 118-131"},"PeriodicalIF":7.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}