Free Radical Biology and Medicine最新文献

{"title":"Methionine sulfoxide reductase A deficiency impairs zebrafish heart regeneration via inhibiting prohibitin 2-Pink1-mediated mitophagy.","authors":"Huicong Li, Xin Yang, Jiayi Li, Yan Zhao, Jieling Liang, Yanmei Liu, Fen Du, Hong Yu, Ruilin Zhang","doi":"10.1016/j.freeradbiomed.2025.09.051","DOIUrl":"10.1016/j.freeradbiomed.2025.09.051","url":null,"abstract":"<p><p>Ischemic heart disease is among the cardiovascular diseases with the highest mortality rates worldwide. Redox homeostasis is critical for a wide range of biological processes, including cardiac injury and repair. Methionine sulfoxide reductase A (MSRA) has been reported as a protective factor for cardiomyocytes both in vivo and in vitro, however, the underlying mechanisms are not fully understood. Here we demonstrated that Msra deficiency in zebrafish results in heart regeneration failure after larval ventricle ablation. Using a proximity labelling assay we identified prohibitin 2a (Phb2a), an ortholog of human PHB2, as a potential substrate of Msra. We further revealed that Pink1-mediated mitophagy is inhibited, thereby impairing heart regeneration in Msra-deficient zebrafish. Moreover, mitophagy is also impeded in Msra-KO HL-1 mouse cardiomyocytes under oxidative stress. Blocking the oxidation of PHB2 by substituting its essential methionine with valine rescues Msra-KO cardiomyocytes from oxidative stress. Taken together, our findings shed light on the role that methionine redox homeostasis plays in the regulation of mitophagy in ischemic heart disease and provide a foundation for the identification of novel therapeutic targets.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"498-510"},"PeriodicalIF":8.2,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191502","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":"Interleukin 13 alleviates traumatic brain injury by promoting pericyte autophagy","authors":"Dongshan Ya ,&nbsp;Bing Guo ,&nbsp;Yanlin Jiang ,&nbsp;Jungang Deng ,&nbsp;Ning Tian ,&nbsp;Xiaoxia Li ,&nbsp;Wei Chen ,&nbsp;Rujia Liao","doi":"10.1016/j.freeradbiomed.2025.09.050","DOIUrl":"10.1016/j.freeradbiomed.2025.09.050","url":null,"abstract":"<div><div>Interleukin 13 (IL13), as a cytokine belonging to the chemokine family, exhibits multiple complex physiological effects. Previous studies have consistently observed its significant role in various types of neural injuries and neurodegenerative diseases, including traumatic brain injury (TBI), through immune modulation and influencing neuroinflammation. However, little is known about its other physiological effects following TBI. In this study, we discovered a previously unreported important effect of IL13. In mouse models of TBI, we found that IL13 can protect against the loss of pericytes in a dose-dependent manner, and this effect was validated in two <em>in vitro</em> injury models relevant to TBI involving pericytes. Neutralizing IL13 levels significantly reversed this protective effect, highlighting the importance of IL13 in protecting pericytes after TBI. Further, through transcriptome analysis combined with pharmacological methods, both <em>in vivo</em> and <em>in vitro</em> experiments revealed that IL13 exerts this protective effect by promoting pericytes autophagy, which is crucial for IL13-induced angiogenesis and neuroprotection after TBI. Additionally, our mechanistic studies revealed that IL13 exerts this protective effect by activating the sirtuin 1 (SIRT1)/the forkhead box O3 (FOXO3) autophagy pathway. This finding provides new insights into the investigation of novel regulatory mechanisms of IL13 in neural injuries and highlights the crucial role of pericytes in TBI.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 384-410"},"PeriodicalIF":8.2,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185055","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":"Redox biology at the intersection of physical activity and air pollution: Mechanisms, consequences, and complexity","authors":"Valentina Jeria-Espinoza ,&nbsp;Carlos Henriquez-Olguin ,&nbsp;Edgardo Opazo-Diaz ,&nbsp;Timoteo Marchini","doi":"10.1016/j.freeradbiomed.2025.09.047","DOIUrl":"10.1016/j.freeradbiomed.2025.09.047","url":null,"abstract":"<div><div>Air pollution and physical inactivity are leading contributors to the global burden of chronic disease and premature mortality. While exercise is a well-established stimulus for physiological adaptations and disease prevention, it also transiently increases reactive oxygen species (ROS) production, which function as essential signals for metabolic remodeling and cellular resilience. In contrast, exposure to air pollution, specifically fine particulate matter (PM_2.5), leads to sustained and uncontrolled ROS production, promoting oxidative damage, inflammation, and cardiometabolic dysfunction.</div><div>This review examines a critical and under-investigated question: How does exercising in polluted environments affect the redox signaling pathways that mediate the health benefits of exercise? We summarize current knowledge at the intersection of exercise physiology, redox biology, and environmental toxicology, with a particular focus on the roles of ROS sources, the scavenger system, and downstream physiological responses. By integrating findings from human and animal studies, we identify factors such as air pollution sources and level of exposure, exercise intensity, and age that shape redox outcomes. We also identify key knowledge gaps to clarify how context-specific redox responses determine whether exercise promotes adaptation or exacerbates pollution-related harm, providing essential insights for future mechanistic research and evidence-based public policies.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 488-497"},"PeriodicalIF":8.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181889","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":"HyPer7: High-level bacterial expression and kinetics showing significant oxidation by peroxynitrite and hypochlorous acid","authors":"Edlaine Linares ,&nbsp;Fernando R. Coelho ,&nbsp;Natalia E. Lemos ,&nbsp;Thiago G.P. Alegria ,&nbsp;Luis ES. Netto ,&nbsp;Ohara Augusto","doi":"10.1016/j.freeradbiomed.2025.09.042","DOIUrl":"10.1016/j.freeradbiomed.2025.09.042","url":null,"abstract":"<div><div>Genetically encoded probes of the HyPer family are regarded as specific for H₂O₂. However, this view may be premature due to the limited studies examining their reactivity with other biologically relevant oxidants under optimized conditions. Peroxynitrite is of particular interest due to its reactivity towards Cys residues, including the catalytic Cys of enzymes involved in cellular signaling. Here, we report the construction of a new plasmid, pET-15b-HyPer7, enabling high-level bacterial expression of HyPer7. The purified HyPer7 presented spectroscopic properties and sensitive response (F₅₀₀/F₄₀₀) to H₂O₂ (2–20 μM) consistent with previously reported data. In contrast, HyPer7 (1 μM) also responded to peroxynitrite and hypochlorous acid (10–50 μM), though less efficiently than to H₂O₂. In all cases, the predominant oxidation product was consistent with HyPer7 disulfide formation, as evidenced by UV–Vis and fluorescence spectra, along with reducing SDS–PAGE; peroxynitrite and hypochlorous acid also yielded secondary products. Stopped-flow kinetics of Hyper7 (1 μM) oxidation by various H₂O₂ (10–200 μM) or peroxynitrite concentrations (10–90 μM) allowed determination of second-order rate constants that differed by one order of magnitude, k_H2O2= (3.60 ± 0.50) x10⁵ M⁻¹ s⁻¹ and k_ONOOH= (2.15 ± 0.03) x 10⁴ M⁻¹ s⁻¹, in phosphate buffer, pH 7.4 at 25^οC. Hypochlorous acid kinetics proved more complex and require further studies; initial assessments suggest a rate constant in the order of 10⁶ M⁻¹ s⁻¹. Overall, our results indicate that HyPer7 is less specific to H₂O₂ than previously assumed. This conclusion likely extends to other members of the HyPer family due to the similar redox-sensitive domain.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 459-468"},"PeriodicalIF":8.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181922","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":"Extracellular ATP dysregulation leads to chronic wounds via the IL-6/NLRP3/ROS axis in patients.","authors":"Marceli C Hanauer, Gilnei B da Silva, Daiane Manica, Bruna C Ozelame, Paula Dallagnol, Rafael A Narzetti, Letícia de S Matias, Vitor A da Rosa, Tais Vidal, Micheli M Pillat, Ariane Zamoner, Aniela P Kempka, Maria E Echevarría-Guanilo, Margarete D Bagatini","doi":"10.1016/j.freeradbiomed.2025.09.046","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.09.046","url":null,"abstract":"<p><p>Chronic wounds are an expensive public health problem that greatly impacts society. The lack of pathophysiological understating impairs the proper management and treatment of this disease. In this study, we aimed to search for the sociodemographic characteristics, biochemical markers, immunological and redox profiles, as well as purinergic signaling in patients with chronic wounds. In addition, we performed a statistical analysis to predict wound chronification by the peripheral biomarkers. Sociodemographically, patients with chronic wounds were predominantly Caucasian males. We found that patients had increased levels of c-protein reactive and blood glucose, and reduction in albumin. The immunological profile analysis showed elevated levels of IL-6. The redox profile confirmed that patients presented an increase in ROS, accompanied by a reduction in levels of PSH and enzymatic activity of SOD. About purinergic signaling, we discovered increased levels of eATP and alterations in the purinergic cascade in PBMCS and platelets. An overexpression of CD39 and NLRP3 was found. Finally, levels of ROS, PSH, IL-6, and eATP were indicated as good predictors of wound chronification. For the first time, we discovered that elevated rates of extracellular ATP are responsible for chronic inflammation and oxidative stress in the chronification process of wounds with deleterious impacts on healing. Monitoring the levels of highlighted peripheral biomarkers may significantly contribute to the treatment of wounds by mitigating the chronification of lesions. We suggest that our findings may apply to clinical outcomes in the treatment of chronic wounds.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181959","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":"Eldecalcitol ameliorates type 2 diabetic osteoporosis by attenuating endothelial ferroptosis via the SOCE/O-GlcNAcylation axis","authors":"Yaling Dai ,&nbsp;Yujun Jiang ,&nbsp;Xiaolin Li ,&nbsp;Junyang Sun ,&nbsp;Hongrui Liu ,&nbsp;Bo Liu ,&nbsp;Minqi Li","doi":"10.1016/j.freeradbiomed.2025.09.041","DOIUrl":"10.1016/j.freeradbiomed.2025.09.041","url":null,"abstract":"<div><div>Accelerated bone degradation and increased risk of fractures, which lead to osteoporosis in patients, are common complications of type 2 diabetes (T2DM), severely impairing the quality of life of patients worldwide. Eldecalcitol (1α,25-dihydroxy-2β-(3-hydroxypropoxy) vitamin D3, or ED71) is a novel active vitamin D analog that has been used in the treatment of postmenopausal osteoporosis. However, its specific regulatory mechanism on endothelial cell function in the context of ferroptosis, as well as its impact on osteogenesis-angiogenesis coupling in type 2 diabetic osteoporosis (T2DOP) remains unclear. The results showed that ED71 plays a role in the impaired osteogenesis and endothelial ferroptosis induced by high glucose and high fat (HGHF), as evidenced by the changes in vascular proliferation, generation and migration, as well as the improvement of osteogenesis of bone marrow mesenchymal stem cells (BMSCs) and the decrease of endothelial ferrous ion (Fe²⁺) level, lipid peroxidation and mitochondrial membrane potential. In addition, ED71 treatment significantly alleviated the impaired osteogenesis and angiogenesis and decreased ferroptosis markers in mouse T2DOP. When exploring the potential mechanism of action, we observed that ED71 suppressed ferroptosis by rescuing store-operated calcium entry (SOCE) mediated calcium signaling and subsequently normalizing aberrant O-GlcNAcylation, and the introduction of the SOCE inhibitor 2-aminoethyl diphenylborinate (2APB) and the OGlcNAcylation inhibitor OSMI-1 counteracted the beneficial effects of ED71 in HGHF-treated endothelial cells. In conclusion, these data suggest that ferroptosis of endothelial cells is associated with T2DOP, and ED71 can regulate ferroptosis of endothelial cells through the SOCE/OGlcNActlation aixs, thereby targeting and modulating bone homeostasis.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 447-458"},"PeriodicalIF":8.2,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174575","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":"Cavidine alleviates paclitaxel-induced peripheral neuropathy by promoting mitochondrial autophagy through inhibiting PKM2-mediated histone lactylation","authors":"Zhenhui Luo ,&nbsp;Zicen Fang ,&nbsp;Xiaomin Cheng ,&nbsp;Shuqi Shi ,&nbsp;Cao Di ,&nbsp;Peikun He ,&nbsp;Haiqiang Wu ,&nbsp;Chuanming Wang ,&nbsp;Wuping Sun","doi":"10.1016/j.freeradbiomed.2025.09.049","DOIUrl":"10.1016/j.freeradbiomed.2025.09.049","url":null,"abstract":"<div><h3>Background</h3><div>Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating adverse effect of chemotherapy, with limited therapeutic options due to unclear mechanisms. Cavidine (CAV), a natural alkaloid, has been shown to possess both anti-inflammatory and neuroprotective properties. However, further research is required to elucidate its role in CIPN and the underlying mechanisms by which it exerts its effects.</div></div><div><h3>Purpose</h3><div>To examine the therapeutic efficacy of CAV in relation to CIPN, with a view to elucidating its underlying mechanism, which is associated with mitophagy and PKM2-mediated histone lactylation.</div></div><div><h3>Methods</h3><div>The post-CAV treatment assessment included the evaluation of mechanical allodynia, thermal hyperalgesia, and footpad immunofluorescence. To identify the regulated pathways of CAV, RNA-seq and lactate metabolomics were performed. The evaluation of mitophagy was conducted through the utilization of immunofluorescence, along with transmission electron microscopy. In addition, the analysis of histone lactylation at H3K18la was undertaken. The use of molecular docking and biolayer interferometry assay confirmed the interactions between CAV-PKM2.</div></div><div><h3>Results</h3><div>CAV significantly alleviated both mechanical and thermal pain, as well as peripheral nerve injury, in mice suffering from CIPN. Mechanistically, CAV suppressed PKM2 activity, reducing lactate accumulation and histone H3K18 lactylation. This inhibition promoted mitochondrial autophagy, evidenced by decreased LC3B-II, upregulated PINK1/Parkin, and reduced p62, and promoted the integration of autophagosomes and lysosomes. Molecular docking and biolayer interferometry assay demonstrated high-affinity binding between CAV and the allosteric site of PKM2.</div></div><div><h3>Conclusion</h3><div>CAV alleviates CIPN by enhancing mitophagy via inhibition of PKM2-driven histone lactylation, thus providing a novel therapeutic strategy for CIPN.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 367-383"},"PeriodicalIF":8.2,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174594","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":"Far infrared therapy improves vascular function by enhancing endothelial function and decreasing arterial stiffness via cytoprotective pathways","authors":"Hala Bagabir ,&nbsp;Omar A. Mohammad ,&nbsp;Chim C. Lang ,&nbsp;Albena T. Dinkova Kostova ,&nbsp;John D. Hayes ,&nbsp;Sharadha Dayalan Naidu ,&nbsp;Kevin Roth ,&nbsp;Faisel Khan","doi":"10.1016/j.freeradbiomed.2025.09.039","DOIUrl":"10.1016/j.freeradbiomed.2025.09.039","url":null,"abstract":"<div><h3>Background</h3><div>Far-infrared radiation (FIR), an invisible part of the electromagnetic spectrum, is recognised for its potential therapeutic effects, particularly in promoting cardiovascular health. It has been proposed that FIR therapy enhances endothelial function and reduces arterial stiffness—both key markers of cardiovascular integrity. This study aims to elucidate the underlying mechanisms by which FIR therapy influences vascular function, specifically examining its impact on redox-associated gene expression and vascular responses in healthy subjects.</div></div><div><h3>Methods</h3><div>In this single-blinded, pilot study, 50 healthy participants were subjected to receive either FIR radiation, heat treatment or a placebo treatment to the upper back. Vascular function was assessed by measuring endothelial function using laser Doppler imaging with iontophoresis and assessing arterial stiffness via SphygmoCor. Gene expression analysis was performed on peripheral blood mononuclear cells (PBMCs), focusing on redox-associated cytoprotective genes and nitric oxide synthase (NOS).</div></div><div><h3>Results</h3><div>FIR radiation led to a significant enhancement in endothelial function and a reduction in arterial stiffness in healthy individuals. Gene expression analyses demonstrated an upregulation of cytoprotective genes, including NOS3, TXNRD1 and HSP70, post-FIR radiation.</div></div><div><h3>Conclusions</h3><div>FIR radiation has been shown to effectively enhance vascular function by improving endothelial function and decreasing arterial stiffness, which likely occurs through activation of cytoprotective pathways. This study suggests that FIR therapy could serve as a non-invasive modality to support cardiovascular health. These results offer valuable biochemical insights into the vascular protective effects of FIR and highlight its potential as a therapeutic strategy for cardiovascular disease prevention.</div></div><div><h3>Objective</h3><div>Aim: The primary aim of this study is to investigate the effect of localised FIR radiation on vascular function, in particular, endothelial function and arterial stiffness in healthy subjects. Endothelial function was examined using LDI combined with the iontophoresis of ACh and SNP, and using circulatory biomarkers for endothelial cells function and oxidation, while arterial stiffness was assessed through the AI@75 %. Hypothesis: The hypothesis of this study is that FIR confers beneficial effects on endothelial function and arterial stiffness through antioxidative and anti-inflammatory mechanisms, mediated in part by the upregulation of cytoprotective genes.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 438-446"},"PeriodicalIF":8.2,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148553","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":"Pro-inflammatory and oxidative responses to burn pit relevant desert particulate matter in macrophages: A role for TLR2 signaling","authors":"Brian J. Day,&nbsp;Jie Huang,&nbsp;Niccolette Schaunaman,&nbsp;Gregory P. Downey,&nbsp;Hong Wei Chu","doi":"10.1016/j.freeradbiomed.2025.09.035","DOIUrl":"10.1016/j.freeradbiomed.2025.09.035","url":null,"abstract":"<div><div>Particulate matter (PM) exposure is linked to many respiratory diseases such as asthma, yet the underlying mechanisms remain unclear. A large number of warfighters deployed to Afghanistan and Iraqi have developed deployment related respiratory disease. This study investigates the effects of burn pit-relevant desert PM from Afghanistan (APM) and comparative desert PM from China Lake, California (CPM) on oxidative stress and pro-inflammatory responses in macrophages. Using mouse monocyte cell line and primary bone marrow-derived macrophages (BMDMs) with or without Toll-like Receptor 2 (TLR2) deficiency, we assessed nitric oxide (NO^.), hydrogen peroxide (H₂O₂), and cytokine production using biochemical assays, enzyme-linked immunosorbent assay (ELISA), pharmacological and genetic modulation, and bulk RNA sequencing. APM was more cytotoxic than CPM in monocytes. Both PMs increased H₂O₂ levels, with acellular conditions generating higher H₂O₂ levels, which was catalase-sensitive and attenuated by metal chelation. APM induced stronger NO^. and cytokine C-X-C motif chemokine ligand 1 (CXCL1) responses than CPM, with NO^. production attenuated by the nitric oxide synthase (NOS) inhibitor L-N^G-nitroarginine methyl ester (LNAME), which also prevented cytotoxicity. TLR2 activation via agonist Pam3CSK4 enhanced NO^. and CXCL1, while inhibition with antagonist C29 or TLR2 knockout partially suppressed APM-induced responses. Bulk RNA sequencing revealed that APM upregulated M1 pro-inflammatory polarization markers, many of which were significantly reduced in TLR2-deficient BMDMs. These findings demonstrate that APM exposure of monocytes/macrophages elicits stronger oxidative and pro-inflammatory responses than CPM, partially mediated through TLR2 signaling. This study provides mechanistic insight into deployment-related PM exposure and identifies potential therapeutic targets to mitigate inflammation in affected individuals.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 330-337"},"PeriodicalIF":8.2,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148578","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":"MiR-743a-3p-mediated hepatic GSTM1 elimination aggravates acetaminophen-induced acute liver injury by inhibiting Sp1 nuclear translocation and SIRT1 expression","authors":"Tian-tian Xu ,&nbsp;Yan Pan ,&nbsp;Yue Jin ,&nbsp;Qin-chao Ding ,&nbsp;Fei-wei Cao ,&nbsp;Rui Guo ,&nbsp;Qin Zhu ,&nbsp;Cai-juan Si ,&nbsp;Qing Song ,&nbsp;Song-tao Li","doi":"10.1016/j.freeradbiomed.2025.09.045","DOIUrl":"10.1016/j.freeradbiomed.2025.09.045","url":null,"abstract":"<div><div>Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury (DILI), and glutathione S-transferase mu 1 (GSTM1), a phase II enzyme involved in drug metabolism and detoxification, is associated with DILI incidence. However, the role of hepatic GSTM1 in APAP-induced liver injury is not fully understood. This study aimed to explore the role of hepatic GSTM1 in APAP-induced hepatotoxicity. A mouse model of APAP-induced liver injury was employed, and liver-specific GSTM1 and/or miR-743a-3p silencing was achieved via adeno-associated virus-8 (AAV8)-mediated RNA delivery. Our data showed that GSTM1 expression was significantly downregulated in APAP-treated mice. APAP induced miR-743a-3p upregulation, which directly suppressed GSTM1 expression, exacerbating liver injury, oxidative damage, and inflammation. Liver-specific miR-743a-3p knockdown rescued GSTM1 knockdown and mitigated liver injury. Mechanistically, GSTM1 interacted with Sp1 and promoted its S-glutathionylation. Loss of GSTM1 decreased Sp1 S-glutathionylation, impairing its nuclear translocation and transcriptional activity, which interfered with sirtuin 1 (SIRT1) expression. Activation of SIRT1 significantly alleviated GSTM1 knockdown-induced liver injury. Our findings suggest that miR-743a-3p-mediated GSTM1 silencing exacerbates APAP-induced liver injury through disruption of the GSTM1-Sp1-SIRT1 axis.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 301-315"},"PeriodicalIF":8.2,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148592","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}