Free Radical Biology and Medicine最新文献

{"title":"Fibroblast growth factor receptor inhibitors ameliorate metabolic dysfunction-associated steatohepatitis by modulating the glycine-glutathione-gut microbiota axis","authors":"Hailong Li ,&nbsp;Xiaoman Ye ,&nbsp;Yayue Hu ,&nbsp;Yingjun Wang ,&nbsp;Yuting Ding ,&nbsp;Ying Yang ,&nbsp;Ruiqi Mao ,&nbsp;Xi Wu ,&nbsp;Huixuan Dong ,&nbsp;Kaijun Qiu ,&nbsp;Xiaohe Li ,&nbsp;Honggang Zhou ,&nbsp;Guang Yang ,&nbsp;Fubao Zhang ,&nbsp;Cheng Yang","doi":"10.1016/j.freeradbiomed.2025.08.044","DOIUrl":"10.1016/j.freeradbiomed.2025.08.044","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease characterized by hepatic steatosis, inflammation, and fibrosis. Dysregulation of fibroblast growth factor receptor (FGFR) signaling is closely associated with various liver diseases, but its role in hepatic metabolism remains unclear. In this study, we developed a small-molecule FGFR inhibitor, CP0813, and evaluated its therapeutic potential in three diet-induced MASH mouse models. Using multi-omics analyses (metabolomics, transcriptomics, and microbiomics), we explored the genetic and metabolic features of MASH as well as the mechanisms of action of CP0813. The results showed that CP0813 inhibited all four FGFR subtypes by over 90 % and significantly improved hepatic steatosis, inflammation, and fibrosis in MASH mice. It exerted antifibrotic effects by inhibiting the FGFR and Transforming growth factor-β (TGF-β)/Smad signaling pathways. Multi-omics analysis further revealed that CP0813 improved MASH by regulating glycine metabolism, glutathione synthesis, and the gut microbiota, with significant interconnections at the genetic, metabolite, and microbial levels. In conclusion, this study not only elucidated the critical role of the FGFR signaling pathway in the pathogenesis of MASH but also provided strong scientific evidence and a potential drug candidate for the development of novel therapeutic strategies for MASH, holding important implications for clinical translation.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 410-425"},"PeriodicalIF":8.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144904232","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":"CO-PERK-IRG1 axis attenuates oxidative stress and ferroptosis in hepatic ischemia-reperfusion injury","authors":"Jeongmin Park ,&nbsp;Min Zheng ,&nbsp;Jeong Heon Gong ,&nbsp;LiHua Jin ,&nbsp;Stefan W. Ryter ,&nbsp;Yeonsoo Joe ,&nbsp;Hun Taeg Chung","doi":"10.1016/j.freeradbiomed.2025.08.042","DOIUrl":"10.1016/j.freeradbiomed.2025.08.042","url":null,"abstract":"<div><div>Hepatic ischemia-reperfusion injury (IRI) can arise as the consequence of surgical procedures, including liver transplant. Hepatic IRI is characterized by oxidative stress, inflammation, and activation of multiple regulated cell death pathways (RCD). Among RCD, ferroptosis is driven by enhanced lipid peroxidation and reactive oxygen species (ROS) formation. Carbon monoxide (CO), which can exert cytoprotective and anti-inflammatory properties, can mitigate IRI in various pre-clinical models when applied at low concentration, though the underlying mechanisms remain poorly understood. In this study, we describe a critical role of protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling in the protective effects of CO against oxidative stress and ferroptosis. We demonstrate that CO-induced PERK activation phosphorylates Nrf2, a master regulator of the cellular antioxidant response, leading to upregulation of immune-responsive gene 1 (IRG1) expression in both Kupffer cells (KCs) and hepatocytes. IRG1-derived itaconate production suppressed ROS accumulation and ferroptosis by enhancing GPX4 levels, while reducing ACSL4 and PTGS2 expression. Genetic interference of PERK or Nrf2 using siRNA or knockout mice abolished CO-mediated IRG1 induction and protection against ferroptosis, highlighting the indispensable role of this pathway.</div><div>Furthermore, in an <em>in vivo</em> model of hepatic IRI, CO treatment significantly reduced inflammation, histopathological damage, and ferroptosis in a manner dependent on the PERK-Nrf2-IRG1 axis. These findings establish the PERK-Nrf2-IRG1-itaconate pathway as a novel therapeutic target for hepatic IRI and potentially other ferroptosis-driven conditions.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 253-266"},"PeriodicalIF":8.2,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889954","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":"Multi-target renal protection in AKI: Exercise-mediated coordination of AMPK energy homeostasis, mTOR autophagy regulation, and NF-κB inflammatory control","authors":"Xishuai Wang ,&nbsp;Zhixin Li ,&nbsp;Cong Liu ,&nbsp;Kangli Du ,&nbsp;Lijia Hou ,&nbsp;Yuehui Zhou ,&nbsp;Xiliang Kong ,&nbsp;Lunan Zhao ,&nbsp;Jiakang Sun ,&nbsp;Depeng Dong ,&nbsp;Han Zhou ,&nbsp;Yixuan Liu ,&nbsp;Zhenxing Huang ,&nbsp;Xiaodi Sun ,&nbsp;Xiaoyun Li ,&nbsp;Jiale Meng ,&nbsp;Ganshen Wang ,&nbsp;Yuhan Wang ,&nbsp;Shengkun Sun ,&nbsp;Juncheng Song ,&nbsp;Fangmin Zhou","doi":"10.1016/j.freeradbiomed.2025.08.030","DOIUrl":"10.1016/j.freeradbiomed.2025.08.030","url":null,"abstract":"<div><h3>Background</h3><div>Aerobic exercise (AE) confers protection against acute kidney injury (AKI), but mechanisms remain incompletely elucidated. We investigated how AE preconditioning protects against sepsis-induced AKI through transcriptomic reprogramming, inflammatory regulation, autophagy modulation, and metabolic adaptation.</div></div><div><h3>Methods</h3><div>Mice were subjected to 4-week AE before AKI induction. We quantified renal function biomarkers, oxidative stress markers, cytokines, and metabolic parameters, performed transcriptomic analysis, and validated mechanisms using mTOR agonist MHY1485.</div></div><div><h3>Results</h3><div>AE preconditioning significantly increased survival rates and attenuated AKI by reducing inflammatory and oxidative damage. It significantly improved the renal dysfunction marker (blood urea nitrogen, creatinine, uric acid, and glomerular filtration rate) levels and improved metabolism by increasing the ATP/ADP ratio, NAD⁺/NADH ratio, and phosphocreatine level and decreasing lactate accumulation. Transcriptomic profiling revealed substantial gene expression alterations in the LPS-induced AKI group (ALI vs. Con groups), with 3595 differentially expressed genes (DEGs) that were enriched in AMPK, mTORC1, NF-κB, and TNF pathways. However, AE preconditioning induced transcriptomic reprogramming characterized by 392 DEGs (ALI vs. AE + ALI groups), which were significantly enriched in AMPK, mTORC1 and NF-κB signaling pathways. Exercise ameliorated AKI through three synergistic mechanisms: (1) AMPK activation restored energy homeostasis by enhancing PGC-1α-mediated mitochondrial biogenesis and PPARα/CPT1a-driven fatty acid oxidation; (2) mTORC1 activation suppressed excessive autophagy via ULK1-ATG13-FIP200 complex inhibition; and (3) NF-κB inhibition was achieved through dual suppression of IL-1R1/TAK1 and TLR3/MyD88 pathways, reducing pro-inflammatory cytokines. Notably, mTOR activation by MHY1485 markedly increased survival rates, attenuated renal injury, promoted energy metabolism, and suppressed excessive autophagy.</div></div><div><h3>Conclusions</h3><div>AE exerts multi-target nephroprotection in AKI by regulating AMPK-mediated metabolic reprogramming, mTOR-dependent autophagy control, and NF-κB inflammatory suppression. This study delineate the molecular basis of exercise-induced renal protection and identifies mTOR as a potential therapeutic target for AKI.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 397-409"},"PeriodicalIF":8.2,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144904231","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":"Beyond phototoxicity: The dark side of new methylene blue on mitochondrial and cellular bioenergetics","authors":"Eduardo Makiyama Klosowski ,&nbsp;Byanca Thais Lima de Souza ,&nbsp;Letícia Fernanda Nanami ,&nbsp;Mariane Carneiro da Silva ,&nbsp;Márcio Shigueaki Mito ,&nbsp;Giovana Natiele Machado Esquissato ,&nbsp;Breno Miguel Joia ,&nbsp;Paulo Vinicius Moreira da Costa Menezes ,&nbsp;Wilker Caetano ,&nbsp;Paulo Cesar de Souza Pereira ,&nbsp;Jeibson Joaquim dos Santos ,&nbsp;Rodolfo Bento Balbinot ,&nbsp;Francielle Pelegrin Garcia ,&nbsp;Danielle Lazarin Bidoia ,&nbsp;Tânia Ueda Nakamura ,&nbsp;Celso Vataru Nakamura ,&nbsp;Emy Luiza Ishii-Iwamoto ,&nbsp;Ana Paula Ferro ,&nbsp;Wanderley Dantas dos Santos ,&nbsp;Osvaldo Ferrarese-Filho ,&nbsp;Rodrigo Polimeni Constantin","doi":"10.1016/j.freeradbiomed.2025.08.037","DOIUrl":"10.1016/j.freeradbiomed.2025.08.037","url":null,"abstract":"<div><div>New methylene blue (NMB) is a phenothiazine dye with recognized photodynamic properties. This study evaluated both light-dependent and intrinsic (light-independent) effects of NMB on mitochondrial function, hepatic metabolism, and cell viability using three models: isolated rat liver mitochondria, ex vivo perfused rat liver, and HepG2 cells. In isolated mitochondria, NMB uncoupled oxidative phosphorylation, decreasing the respiratory control (RC) and ADP/O ratios, even without irradiation. It increased inner membrane permeability, inferred from enhanced oxidation of exogenous NADH, and inhibited mitochondrial swelling. Red-light irradiation exacerbated these effects, leading to inhibition of respiratory chain complexes and F_oF₁-ATP synthase, along with reduced catalase and glutathione reductase activities and depletion of GSH. Oxidative damage was confirmed by elevated lipid peroxidation and protein carbonylation. In perfused liver, NMB disrupted oxygen consumption linked to ATP synthesis and impaired energy-dependent processes such as gluconeogenesis and ammonia detoxification, particularly under fasting. These effects correlated with decreased ATP/ADP and ATP/AMP ratios, potentially impairing pyruvate carboxylase and carbamoyl phosphate synthetase I. In livers from fed rats, NMB stimulated glycolysis and glycogenolysis, while in fasting conditions it also enhanced fructolysis—likely as a compensatory response to mitochondrial dysfunction. Additionally, NMB-mediated NADH oxidation may raise NAD⁺ availability and support citric acid cycle activity. Membrane destabilization and enzyme leakage occurred even without light, indicating strong intrinsic cytotoxicity. Red-light exposure further intensified hepatic damage, likely due to <em>in situ</em> activation of the photosensitizer. In HepG2 cells, NMB reduced cell viability in a concentration-dependent manner, with no significant difference between irradiated and non-irradiated conditions—highlighting a pronounced dark toxicity. These results demonstrate that NMB impairs mitochondrial function and hepatic metabolism through both photodynamic and non-photodynamic mechanisms. Given the consistent toxicity across all models, including in the absence of light, NMB's therapeutic potential as a photosensitizer appears limited, warranting careful toxicological assessment before clinical application.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 314-338"},"PeriodicalIF":8.2,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144895258","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":"Knockdown of MiD49 and MiD51 alleviates collagen-induced arthritis and suppresses mitophagy and fatty acid oxidation (FAO) in rheumatoid arthritis fibroblast-like synoviocytes","authors":"Jiaqing Liu ,&nbsp;Cheng Zhang ,&nbsp;Ruicong Ma ,&nbsp;Chunlai Yin ,&nbsp;Jinyi Ren ,&nbsp;Siwen Yang ,&nbsp;Ying Zhao ,&nbsp;Yawei Tang ,&nbsp;Jing Wei ,&nbsp;Xia Li","doi":"10.1016/j.freeradbiomed.2025.08.034","DOIUrl":"10.1016/j.freeradbiomed.2025.08.034","url":null,"abstract":"<div><div>Increasing evidence confirms that imbalances in mitochondrial dynamics can impair mitochondrial function, thereby disrupting cellular homeostasis and potentially contributing to a variety of diseases. This study investigated whether mitochondrial dynamics proteins of 49 and 51 kDa (MiD49 and MiD51, MiDs) contribute to the maintenance of the abnormal functions of fibroblast-like synoviocytes (FLS), thereby participating in the pathological process of rheumatoid arthritis (RA), and to elucidate the specific mechanisms. We found that MiDs were significantly upregulated in the FLS of synovial tissues from RA patients and collagen-induced arthritis (CIA) models, as well as in the serum of RA patients. The elevated expression of MiDs in RA serum exhibited a positive correlation with clinical markers. Moreover, knocking down MiD49 or MiD51 alleviated CIA symptoms and attenuated the aggressive behavior of RA-FLS. We found the potential interactions between MiDs and the PTEN-induced kinase 1 (PINK1)-PARK2 E3 ubiquitin-protein ligase (Parkin) pathway, as well as the correlation between the PINK1-Parkin pathway and lipid metabolism, were revealed through protein-protein interaction (PPI) analysis. The PINK1-Parkin-dependent mitophagy and carnitine palmitoyltransferase-1A (CPT-1A) mediated-fatty acid β oxidation (FAO) were impaired following siRNA-mediated knockdown of MiD49 or MiD51. We found that siRNA-mediated knockdown of PINK1 and Parkin effectively reversed the aggressive phenotype of RA-FLS. Finally, we further verified that shRNA targeting MiD49 or MiD51 inhibited Pink1-Parkin-dependent mitophagy and CPT-1A-regulated FAO in FLS derived from the synovial tissues of CIA models. Our study highlights the involvement of MiDs-mediated mitochondrial dynamics dysfunction helps maintain the invasiveness of FLS, and thereby participates in the pathogenesis of RA. These findings provide a theoretical basis for the development of potential therapies for RA in the future.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 514-531"},"PeriodicalIF":8.2,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144922496","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":"Exercise training ameliorates high-fat diet-induced skeletal muscle atrophy and ferroptosis via downregulation of STING","authors":"Zujie Xu ,&nbsp;Zheying Ma ,&nbsp;Huiqian Ren ,&nbsp;Yaming Yang ,&nbsp;Xiaoqin Zhao ,&nbsp;Shou Pan ,&nbsp;Jie Tang ,&nbsp;Bing Zhang","doi":"10.1016/j.freeradbiomed.2025.08.043","DOIUrl":"10.1016/j.freeradbiomed.2025.08.043","url":null,"abstract":"<div><h3>Background</h3><div>High-fat diet (HFD)-induced sarcopenic obesity can lead to reductions in muscle fiber diameter, enhanced protein degradation, and various forms of cell death. Exercise training has been shown to alleviate HFD-induced muscle atrophy. However, the underlying mechanism remains unclear. Stimulator of interferon genes (STING) is involved in ferroptosis and various forms of muscle atrophy. This study aimed to investigate the role of STING in exercise training against HFD-induced skeletal muscle atrophy.</div></div><div><h3>Methods</h3><div>In vivo, HFD-fed mice were subjected to exercise training and were intraperitoneally injected with the STING agonist diABZI or selective STING inhibitor C-176 for 8 weeks. In vitro, the differentiated C2C12 myotubes were treated with palmitic acid (PA), followed by interventions with Ferrostatin-1 (Fer-1), Erastin, diABZI or C-176. Grip strength test, body composition analysis, serum assay, histology analysis, dihydroethidium staining, transmission electron microscopy, myosin heavy chain staining, mitochondrial membrane potential, Western blot, and real-time quantitative PCR were performed.</div></div><div><h3>Results</h3><div>In vivo, exercise training significantly reduced the mRNA and protein expression of STING and ameliorated skeletal muscle atrophy and lipid peroxidation associated ferroptosis in HFD-fed mice. The STING agonist diABZI blunted the alleviative effect of exercise training in HFD-induced skeletal muscle atrophy and ferroptosis. The selective STING inhibitor C-176 and exercise training synergistically alleviated HFD-induced skeletal muscle atrophy and ferroptosis. In vitro, the ferroptosis inhibitor Fer-1 partially rescued PA-triggered C2C12 myotubes atrophy and ferroptosis, whereas the ferroptosis activator Erastin aggravated myotubes atrophy and ferroptosis. diABZI exacerbated PA-induced C2C12 myotubes atrophy and ferroptosis. Erastin impaired the ameliorative effect of C-176 in PA-induced C2C12 myotubes atrophy and ferroptosis.</div></div><div><h3>Conclusions</h3><div>Exercise training effectively suppressed HFD-mediated upregulation of STING in skeletal muscle. STING is a response factor for the alleviative effect of exercise training in HFD-induced skeletal muscle atrophy and ferroptosis.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 373-383"},"PeriodicalIF":8.2,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144904229","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":"Epimedokoreanin B blocks autophagic flux to inhibit progression of triple negative breast cancer through targeting MCOLN1/TRPML1 channel","authors":"Chenyang Zhao ,&nbsp;Peng Zhang ,&nbsp;Xiaojuan Yang ,&nbsp;Miao Liu ,&nbsp;Zhirong Guan ,&nbsp;Bin Ma ,&nbsp;Xiangguo Duan ,&nbsp;Chunxia Su","doi":"10.1016/j.freeradbiomed.2025.08.041","DOIUrl":"10.1016/j.freeradbiomed.2025.08.041","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) remains a highly malignant subtype with limited therapeutic options. Here, Epimedokoreanin B (EKB), a flavonoid derived from Epimedium brevicornum, is identified as a potent inhibitor of TNBC progression. Mechanistically, EKB directly binds MCOLN1/TRPML1, thereby promoting lysosomal Ca²⁺ efflux and impairing lysosomal acidification. This disruption specifically blocks autophagosome-lysosome fusion, leading to autophagic flux inhibition and subsequent accumulation of intracellular oxidants, including hydrogen peroxide (H₂O₂), related peroxides, and mitochondrial superoxide (O2•-). Importantly, the resulting oxidative stress acts as a critical mediator, ultimately triggering apoptosis. The specificity of the EKB-MCOLN1/TRPML1 interaction was validated through molecular docking, Cellular Thermal Shift Assay (CETSA), and pharmacological MCOLN1/TRPML1inhibition. In TNBC mouse models, EKB treatment significantly suppressed primary tumor growth and, notably, reduced pulmonary metastasis. Additionally, no systemic toxicity was observed. Furthermore, EKB treatment reprogrammed the tumor immune microenvironment, evidenced by increased infiltration of CD8⁺T cells and M1 macrophages alongside reduced immunosuppressive subsets. Taken together, these results establish EKB as a promising therapeutic candidate that couples autophagy blockade with immune activation, and highlight oxidative stress as a significant contributing mechanism underlying its anticancer effects.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 222-237"},"PeriodicalIF":8.2,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144886991","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":"DNA methylation signature of oxidative stress and its mediating role in response to metal exposure","authors":"Yufei Wang ,&nbsp;Jiake Zhang ,&nbsp;Wending Li ,&nbsp;Yi Jiang ,&nbsp;Xuedan Xu ,&nbsp;Qin Jiang ,&nbsp;Yutong You ,&nbsp;Yang Xiao ,&nbsp;Chengyong Jia ,&nbsp;Min Zhang ,&nbsp;Chong Liu ,&nbsp;Qiang Zeng ,&nbsp;Yu Yuan ,&nbsp;Meian He ,&nbsp;Xiaomin Zhang ,&nbsp;Huan Guo ,&nbsp;Min Zhou ,&nbsp;Chaolong Wang ,&nbsp;Weihong Chen ,&nbsp;Tangchun Wu ,&nbsp;Pinpin Long","doi":"10.1016/j.freeradbiomed.2025.08.039","DOIUrl":"10.1016/j.freeradbiomed.2025.08.039","url":null,"abstract":"<div><div>Metal exposure could induce oxidative stress, yet the underlying epigenetic mechanisms remain unclear. Herein, we aimed to investigate the DNA methylation signatures associated with oxidative stress biomarkers, including 8-hydroxyguanine (8-OHdG) and 8-iso-prostaglandin-F2α (8-iso-PGF2α), and evaluate their mediating role in metal-induced oxidative stress. A genome-wide DNA methylation association study was conducted in discovery panel (Shiyan, N = 155) with validation in an independent replication panel (Wuhan-Zhuhai, N = 50). We identified 24 differentially methylated positions (DMPs) associated with 8-OHdG (<em>P</em> &lt; 1 × 10⁻⁵), 17 of which were replicated (<em>P</em> &lt; 0.05), along with one validated DMP associated with 8-iso-PGF2α. Two-sample Mendelian randomization analyses supported the causal role of cg15457217 (<em>WDFY1</em>) for 8-OHdG and cg16689883 (<em>LOC284930</em>) for 8-iso-PGF2α. Among the 18 replicated DMPs, five were significantly associated with the expression levels of their annotated genes (<em>KIDINS220</em>, <em>SBF2</em>, <em>DENND1A</em>, <em>PIWIL4</em>, <em>KAT6B</em>). Urinary levels of individual metals (e.g., arsenic, cadmium, molybdenum, strontium) and metal mixtures (assessed by weighted quantile sum regression) were positively associated with both oxidative stress biomarkers. Mediation analyses revealed that 14 replicated DMPs mediated 12.54–33.44 % of the associations for 8-OHdG and 12.60–13.83 % for 8-iso-PGF2α. Notably, cg06197624 (<em>SMIM20</em>) and cg09953898 (<em>KIDINS220</em>) exhibited a significant inverse association with 8-OHdG (<em>FDR</em> &lt; 0.05) and mediated up to 33.44 % of the effect of metal exposure on oxidative DNA damage. These findings demonstrated the mediating role of DNA methylation in metal-induced oxidative stress, highlighting the epigenetic loci involved in redox-related biological responses. Further studies with larger sample sizes and longitudinal assessments are warranted to validate our findings.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 211-221"},"PeriodicalIF":8.2,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144886990","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":"Inhibition of ALOX5-dependent ferroptosis by 6-C-methylquercetin: a potential therapeutic approach for alleviating rheumatoid arthritis","authors":"Beixi Jia,&nbsp;Siyuan Zhou,&nbsp;Mengyang Liu,&nbsp;Mengyao Zhang,&nbsp;Xinyue Jiang,&nbsp;Xueyang Guo,&nbsp;Yuefeng Bi","doi":"10.1016/j.freeradbiomed.2025.08.032","DOIUrl":"10.1016/j.freeradbiomed.2025.08.032","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA), a chronic autoimmune disease, requires novel therapeutic targets. Ferroptosis, an iron-dependent form of regulated cell death, is closely linked to RA pathogenesis through its mediation of inflammation, oxidative stress, and lipid peroxidation. ALOX5, a member of the lipoxygenase family, is an important regulator of ferroptosis. Inhibiting ALOX5-dependent ferroptosis in joint synovial tissue may thus offer a potential therapeutic strategy for RA. Natural compound 6-C-Methylquercetin possesses robust anti-inflammatory and antioxidant properties, and network pharmacology identifies ALOX5 as its key target against RA. This study aimed to elucidate the pathogenic roles of ALOX5-mediated ferroptosis in RA and evaluate the therapeutic potential of 6-C-methylquercetin. Through <em>in vivo</em> and <em>in vitro</em> experiments, ALOX5 overexpression in RA fibroblast-like synoviocytes (FLSs) was shown to activate ferroptosis, characterized by elevated levels of MDA, lipid ROS, ROS, Fe²⁺, ACSL3, NOX1, and COX2, alongside reduced GSH/GSSG ratio and GPX4 expression. Conversely, 6-C-methylquercetin ameliorated RA progression by targeting ALOX5 to disrupt the ALOX5-COTL1 interaction, inhibit aberrant PI3K/AKT pathway activation, and consequently suppress ferroptosis and pro-inflammatory cytokine secretion in FLSs. Further molecular computational simulations, surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA) validated ALOX5 as a direct target of 6-C-methylquercetin, and high-affinity binding was achieved through the B-ring C4′-hydroxyl group of 6-C-methylquercetin, forming a hydrogen-bond network with amino acid residue (ARG411) in the ALOX5 active site. In the collagen-induced arthritis (CIA) mouse model, 6-C-methylquercetin effectively alleviated synovial inflammation and ankle joint damage, reconfirmed its inhibitory effect on ferroptosis, and demonstrated favorable <em>in vivo</em> biosafety. These findings establish ALOX5-driven ferroptosis as a novel therapeutic target for RA, while 6-C-methylquercetin demonstrates dual anti-ferroptotic and anti-inflammatory efficacy through specific ALOX5 inhibition, highlighting its translational promise.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 153-169"},"PeriodicalIF":8.2,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144880024","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":"FATP5 deficiency alleviates MASH via remodeling hepatic lipid composition to suppress ferroptosis","authors":"Yiran Liu ,&nbsp;Mingyu Zhang ,&nbsp;Chen Zhu ,&nbsp;Yu Zhang ,&nbsp;Yujie Huang ,&nbsp;Suhong Xia ,&nbsp;Jiazhi Liao","doi":"10.1016/j.freeradbiomed.2025.08.035","DOIUrl":"10.1016/j.freeradbiomed.2025.08.035","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatohepatitis (MASH) represents an advanced stage of fatty liver disease characterized by hepatocyte ballooning, cell death, inflammation and fibrosis. Fatty acid transport protein 5 (FATP5), a hepatocyte-specific transmembrane protein, mediates both long-chain fatty acids (LCFAs) uptake and bile acids (BAs)-coenzyme A (CoA) conjugation. While FATP5 upregulation has been documented in MASH patients, its functional role in disease progression through hepatic lipid metabolic regulation remains unclear. In this study, we identified FATP5 elevation both in vitro and in vivo MASH models. Treatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1) significantly attenuated MASH histopathology and steatotic HepG2 cell death. Furthermore, FATP5 deficiency protected against methionine-choline-deficient diet (MCD)-induced MASH in the mouse model and prevented steatotic HepG2 cell deaths through reducing ferroptosis. Notably, we discovered an inverse correlation between FATP5 and stearoyl-CoA desaturase 1 (SCD1) expression. As the rate-limiting enzyme for monounsaturated fatty acid (MUFA) biosynthesis, SCD1 overexpression exhibited ferroptosis resistance in erastin-treated HepG2 cells. Untargeted lipidomics revealed that FATP5 knockdown preferentially reduced pro-ferroptotic polyunsaturated fatty acid (PUFA)-containing lipids. Mechanistically, reduction of PUFA-lipids alleviated suppression of Sterol regulatory element binding protein 1 (SREBP1), subsequently upregulating its transcriptional target SCD1. Finally, we found that adeno-associated virus-mediated SCD1 overexpression in vivo effectively attenuated inflammation and liver injury in MASH by inhibiting hepatic ferroptosis. In conclusion, our findings suggest that FATP5 knockdown alleviates MASH via remodeling hepatic lipid composition to activate the SREBP1/SCD1 axis, thereby inhibiting ferroptosis. The findings also indicate that FATP5 may serve as a potential therapeutic target of MASH.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 170-182"},"PeriodicalIF":8.2,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144887108","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}