Pub Date : 2026-03-16Epub Date: 2026-01-29DOI: 10.1016/j.freeradbiomed.2026.01.056
Ziqing Chen , Xing Li , Jialei Zhong , Guochang Chen , Dinghong Min , Jiawen Fan , Jinwei Shang , Gehua Zhu , Peng Hua , Mingzhuo Liu , Guanghua Guo
Metformin (Met), a first-line therapeutic agent for type 2 diabetes, has been widely recognized for its antifibrotic properties in various pathological conditions. However, its effects on hypertrophic scars (HS) and the underlying mechanisms remain insufficiently explored. The present study aimed to elucidate the role of metformin in HS and to investigate its associated molecular mechanisms. Both in vitro and in vivo experiments demonstrated that metformin markedly inhibited the proliferation, migration, and collagen deposition of hypertrophic scar fibroblasts (HSFs), and alleviated HS formation in a rabbit ear model. Mechanistic investigations further revealed that these effects were closely associated with the downregulation of ribonucleotide reductase regulatory subunit M2 (RRM2). Notably, reduced RRM2 expression suppressed the production of glutathione synthetase (GSS), thereby impairing glutathione (GSH) synthesis. This, in turn, indirectly downregulated glutathione peroxidase 4 (GPX4), leading to the intracellular accumulation of peroxides and triggering ferroptosis in vivo and in vitro. Collectively, these findings suggest that metformin may attenuate HS fibrosis by inducing HSFs ferroptosis through the RRM2/GSS/GPX4 signaling axis. This study not only expands the potential clinical application of metformin in the treatment of skin fibrosis but also provides a theoretical foundation for the development of novel anti-scar therapeutics.
{"title":"Metformin targets RRM2/GSS/GPX4 axis to induce fibroblast ferroptosis: A foreground strategy against hypertrophic scarring","authors":"Ziqing Chen , Xing Li , Jialei Zhong , Guochang Chen , Dinghong Min , Jiawen Fan , Jinwei Shang , Gehua Zhu , Peng Hua , Mingzhuo Liu , Guanghua Guo","doi":"10.1016/j.freeradbiomed.2026.01.056","DOIUrl":"10.1016/j.freeradbiomed.2026.01.056","url":null,"abstract":"<div><div>Metformin (Met), a first-line therapeutic agent for type 2 diabetes, has been widely recognized for its antifibrotic properties in various pathological conditions. However, its effects on hypertrophic scars (HS) and the underlying mechanisms remain insufficiently explored. The present study aimed to elucidate the role of metformin in HS and to investigate its associated molecular mechanisms. Both in vitro and in vivo experiments demonstrated that metformin markedly inhibited the proliferation, migration, and collagen deposition of hypertrophic scar fibroblasts (HSFs), and alleviated HS formation in a rabbit ear model. Mechanistic investigations further revealed that these effects were closely associated with the downregulation of ribonucleotide reductase regulatory subunit M2 (RRM2). Notably, reduced RRM2 expression suppressed the production of glutathione synthetase (GSS), thereby impairing glutathione (GSH) synthesis. This, in turn, indirectly downregulated glutathione peroxidase 4 (GPX4), leading to the intracellular accumulation of peroxides and triggering ferroptosis in vivo and in vitro. Collectively, these findings suggest that metformin may attenuate HS fibrosis by inducing HSFs ferroptosis through the RRM2/GSS/GPX4 signaling axis. This study not only expands the potential clinical application of metformin in the treatment of skin fibrosis but also provides a theoretical foundation for the development of novel anti-scar therapeutics.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 489-504"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097078","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}
Ferroptosis is a non-accidental form of cell death driven by lipid peroxidation and critically controlled by the selenoenzyme Glutathione Peroxidase 4 (GPx4). By integrating molecular modeling, redox thermodynamics, and enzymatic evidence, we propose that ferroptosis is governed by the redox potential of the glutathione couple, elevating current mechanistic descriptions to a quantitative physical–chemical framework. The terminal step of the GPx4 catalytic cycle—responsible for enzyme regeneration and oxidized glutathione (GSSG) formation—is intrinsically endergonic, and its driving force declines continuously as the glutathione redox potential becomes less reducing. As a result, GPx4 activity decreases linearly in accordance with Nernstian principle, independently of discrete inhibitory events. Within this framework, ferroptosis is not initiated by a discrete molecular trigger or canonical signaling cascade; rather, it emerges when a critical biological threshold is surpassed, such that GPx4-dependent detoxification capacity is no longer sufficient to counteract ongoing lipid peroxidation within a given pro-oxidant context. Thus, a discrete cell-death outcome executed by GSSG emerges from the continuous variation of a thermodynamic control variable. This mode of regulation is unique to selenium chemistry and provides a physical–chemical rationale for the indispensability of selenocysteine in the redox control of cellular life and death.
{"title":"A thermodynamic constraint on GPx4 flux links glutathione redox state to ferroptotic commitment","authors":"Fulvio Ursini , Antonella Roveri , Matilde Maiorino , Laura Orian","doi":"10.1016/j.freeradbiomed.2026.01.039","DOIUrl":"10.1016/j.freeradbiomed.2026.01.039","url":null,"abstract":"<div><div>Ferroptosis is a non-accidental form of cell death driven by lipid peroxidation and critically controlled by the selenoenzyme Glutathione Peroxidase 4 (GPx4). By integrating molecular modeling, redox thermodynamics, and enzymatic evidence, we propose that ferroptosis is governed by the redox potential of the glutathione couple, elevating current mechanistic descriptions to a quantitative physical–chemical framework. The terminal step of the GPx4 catalytic cycle—responsible for enzyme regeneration and oxidized glutathione (GSSG) formation—is intrinsically endergonic, and its driving force declines continuously as the glutathione redox potential becomes less reducing. As a result, GPx4 activity decreases linearly in accordance with Nernstian principle, independently of discrete inhibitory events. Within this framework, ferroptosis is not initiated by a discrete molecular trigger or canonical signaling cascade; rather, it emerges when a critical biological threshold is surpassed, such that GPx4-dependent detoxification capacity is no longer sufficient to counteract ongoing lipid peroxidation within a given pro-oxidant context. Thus, a discrete cell-death outcome executed by GSSG emerges from the continuous variation of a thermodynamic control variable. This mode of regulation is unique to selenium chemistry and provides a physical–chemical rationale for the indispensability of selenocysteine in the redox control of cellular life and death.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 394-399"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046370","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}
Pub Date : 2026-03-16Epub Date: 2026-01-23DOI: 10.1016/j.freeradbiomed.2026.01.029
Yi Chen , Zhaoyu Liu , Zesen Mai , Yongbing Zhou , Huiwen Wen , Gaowen Qu , Runhao Zeng , Dongmei Zhu , Yuxiong Lai , Xue Liang
Non-small cell lung cancer (NSCLC) remains a lethal malignancy due to therapy resistance and recurrence. Ferroptosis, a regulated form of cell death, is a promising strategy to overcome cancer drug resistance, yet its mechanisms remain incompletely defined. Here, we report that Immediate Early Response 3 (IER3) is significantly upregulated in NSCLC tumors and linked to advanced stage and poor prognosis. Using IER3-overexpressing and knockout models in A549 and H1299 cells, we found that IER3 promotes NSCLC cell proliferation, migration, and invasion by suppressing ferroptosis. Conversely, IER3 knockout induced ferroptosis and reduced malignancy—effects reversed by the ferroptosis inhibitor Fer-1. Mechanistically, IER3 sustained AKT phosphorylation to inactivate GSK3β, both blocking GSK3β-dependent proteasomal degradation of NRF2 and enhancing its nuclear translocation, which collectively led to the transactivation of downstream ferroptosis-suppressive gene programs. This program maintained glutathione homeostasis, sequestered labile iron, scavenged ROS, and ultimately inhibited lipid peroxidation to counter ferroptosis. Rescue assays confirmed NRF2 overexpression or AKT/GSK3β activation reversed IER3 knockout-induced ferroptosis and viability loss. Additionally, low-IER3 NSCLC tumors were more sensitive to clinical/preclinical agents targeting survival/stress pathways. Collectively, our findings establish IER3 as an NSCLC oncogenic driver—suppressing ferroptosis via AKT/GSK3β/NRF2 to sustain malignancy—highlighting its potential as a prognostic biomarker and therapeutic target for improved NSCLC outcomes.
{"title":"IER3 promotes non-small cell lung cancer malignancy by suppressing ferroptosis via the AKT/GSK3β/NRF2 pathway","authors":"Yi Chen , Zhaoyu Liu , Zesen Mai , Yongbing Zhou , Huiwen Wen , Gaowen Qu , Runhao Zeng , Dongmei Zhu , Yuxiong Lai , Xue Liang","doi":"10.1016/j.freeradbiomed.2026.01.029","DOIUrl":"10.1016/j.freeradbiomed.2026.01.029","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) remains a lethal malignancy due to therapy resistance and recurrence. Ferroptosis, a regulated form of cell death, is a promising strategy to overcome cancer drug resistance, yet its mechanisms remain incompletely defined. Here, we report that Immediate Early Response 3 (IER3) is significantly upregulated in NSCLC tumors and linked to advanced stage and poor prognosis. Using IER3-overexpressing and knockout models in A549 and H1299 cells, we found that IER3 promotes NSCLC cell proliferation, migration, and invasion by suppressing ferroptosis. Conversely, IER3 knockout induced ferroptosis and reduced malignancy—effects reversed by the ferroptosis inhibitor Fer-1. Mechanistically, IER3 sustained AKT phosphorylation to inactivate GSK3β, both blocking GSK3β-dependent proteasomal degradation of NRF2 and enhancing its nuclear translocation, which collectively led to the transactivation of downstream ferroptosis-suppressive gene programs. This program maintained glutathione homeostasis, sequestered labile iron, scavenged ROS, and ultimately inhibited lipid peroxidation to counter ferroptosis. Rescue assays confirmed NRF2 overexpression or AKT/GSK3β activation reversed IER3 knockout-induced ferroptosis and viability loss. Additionally, low-IER3 NSCLC tumors were more sensitive to clinical/preclinical agents targeting survival/stress pathways. Collectively, our findings establish IER3 as an NSCLC oncogenic driver—suppressing ferroptosis via AKT/GSK3β/NRF2 to sustain malignancy—highlighting its potential as a prognostic biomarker and therapeutic target for improved NSCLC outcomes.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 711-724"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046432","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}
Pub Date : 2026-03-16Epub Date: 2026-01-09DOI: 10.1016/j.freeradbiomed.2025.12.060
Youyi Wu , Dan Chen , Xiaohu Wang , Mengyao Song , Jingyi Wu , Shunlong Wu , Kui Liao
Breast cancer is one of the most common malignancies and a leading cause of mortality among women worldwide. Triple-negative breast cancer (TNBC) accounts for 15–20 % of all breast cancer cases and is characterized by poor prognosis, high invasiveness, and a propensity for metastasis. Radiotherapy is a crucial component of multimodal therapy for TNBC, serving primarily as an adjuvant modality following surgery or for local control in locally advanced disease. However, tumor tissues gradually adapt to radiation exposure, leading to the development of radioresistance—a phenomenon where cancer cells survive and proliferate despite radiotherapy, significantly compromising treatment efficacy and patient outcomes. In recent years, numerous studies have reported that the herbal compound dihydroartemisinin (DHA) may serve as a radiosensitizer to enhance tumor sensitivity to radiation while reducing radiotoxicity in surrounding normal tissues. Nevertheless, the underlying mechanisms remain insufficient to meet clinical translation demands. Thus, identifying novel targets and alternative sensitization mechanisms is urgently needed. Here, we report that DHA overcomes acquired radioresistance by orchestrating a novel autophagy-dependent ferroptosis pathway. We demonstrate that DHA directly binds to and promotes the ubiquitination-mediated degradation of GPX4, a key guardian against ferroptosis. This degradation leads to intracellular Fe2+ accumulation and lethal lipid peroxidation. Crucially, we establish that autophagy acts as an essential upstream mechanism enabling GPX4 degradation, thereby bridging DHA-induced stress to ferroptotic execution. Both Atg5 knockdown and pharmacological inhibition of autophagy prevented DHA-induced GPX4 loss and the consequent radiosensitization. Collectively, our findings reveal a previously unrecognized mechanism in which DHA overcomes TNBC radioresistance by co-opting the autophagy pathway to degrade GPX4 and unleash ferroptosis, presenting a promising therapeutic paradigm targeting the autophagy-ferroptosis axis for refractory TNBC.
{"title":"Dihydroartemisinin targets GPX4 to induce autophagy-dependent ferroptosis and reduce radioresistance in triple-negative breast cancer","authors":"Youyi Wu , Dan Chen , Xiaohu Wang , Mengyao Song , Jingyi Wu , Shunlong Wu , Kui Liao","doi":"10.1016/j.freeradbiomed.2025.12.060","DOIUrl":"10.1016/j.freeradbiomed.2025.12.060","url":null,"abstract":"<div><div>Breast cancer is one of the most common malignancies and a leading cause of mortality among women worldwide. Triple-negative breast cancer (TNBC) accounts for 15–20 % of all breast cancer cases and is characterized by poor prognosis, high invasiveness, and a propensity for metastasis. Radiotherapy is a crucial component of multimodal therapy for TNBC, serving primarily as an adjuvant modality following surgery or for local control in locally advanced disease. However, tumor tissues gradually adapt to radiation exposure, leading to the development of radioresistance—a phenomenon where cancer cells survive and proliferate despite radiotherapy, significantly compromising treatment efficacy and patient outcomes. In recent years, numerous studies have reported that the herbal compound dihydroartemisinin (DHA) may serve as a radiosensitizer to enhance tumor sensitivity to radiation while reducing radiotoxicity in surrounding normal tissues. Nevertheless, the underlying mechanisms remain insufficient to meet clinical translation demands. Thus, identifying novel targets and alternative sensitization mechanisms is urgently needed. Here, we report that DHA overcomes acquired radioresistance by orchestrating a novel autophagy-dependent ferroptosis pathway. We demonstrate that DHA directly binds to and promotes the ubiquitination-mediated degradation of GPX4, a key guardian against ferroptosis. This degradation leads to intracellular Fe<sup>2+</sup> accumulation and lethal lipid peroxidation. Crucially, we establish that autophagy acts as an essential upstream mechanism enabling GPX4 degradation, thereby bridging DHA-induced stress to ferroptotic execution. Both Atg5 knockdown and pharmacological inhibition of autophagy prevented DHA-induced GPX4 loss and the consequent radiosensitization. Collectively, our findings reveal a previously unrecognized mechanism in which DHA overcomes TNBC radioresistance by co-opting the autophagy pathway to degrade GPX4 and unleash ferroptosis, presenting a promising therapeutic paradigm targeting the autophagy-ferroptosis axis for refractory TNBC.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 35-50"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951784","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}
Pub Date : 2026-03-16Epub Date: 2026-01-12DOI: 10.1016/j.freeradbiomed.2026.01.016
Zhuolin Du , Xingwu Liu , Yanhan Yang , Xudong Min , Jirui Wei , Yang She , Abudushalamu Abulaiti , Xiayu Jin , Zequn Su , Shizhong Zhang , Jian Liu , Karrie M. Kiang , Gilberto Ka-Kit Leung , Xiaozheng He , Zhiyuan Zhu
Mitochondrial integrity is essential for tumor cell proliferation and survival. Our previous study has demonstrated the oncogenic role of the metabolic enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in glioblastoma (GBM). Given that the non-metabolic function of certain enzymes has been reported, we aim to interrogate whether MTHFD2 has potential roles in mitochondrial integrity and dynamics, especially beyond catabolism. By using multi-faceted approaches including single-cell RNA sequencing, mt-Keima mitophagy flux assays, RNA immunoprecipitation sequencing and luciferase reporter assays, we elucidated a novel, non-canonical function of MTHFD2 in stabilizing mRNA in GBM. We found that MTHFD2 was upregulated in GBM and was enriched in specific tumor subtypes cells such as ependymal-like and OPC-like cells. Knockdown of MTHFD2 profoundly promoted mitochondrial fission that triggered excessive mitophagy and cellular apoptosis. Mechanistically, MTHFD2 directly bound to the 3′-untranslated region (3′-UTR) of TOP2A mRNA and enhanced its stability, implying the RNA binding function of this catabolic enzyme. Overexpression of TOP2A attenuated mitophagy and cellular apoptosis induced by MTHFD2 depletion, indicating a vital role of MTHFD2-TOP2A axis in modulating mitochondrial integrity. Importantly, targeting MTHFD2 impeded GBM growth in orthotopic mouse models, which could be a promising therapeutic strategy. In conclusion, we proposed a non-canonical function of MTHFD2, which bound to and stabilized the mRNA of TOP2A. Targeting MTHFD2 triggered excessive mitophagy and cell apoptosis in GBM via destabilizing TOP2A mRNA.
{"title":"The non-metabolic role of MTHFD2 in regulating mitochondrial fission-dependent mitophagy via stabilizing TOP2A mRNA in glioblastoma","authors":"Zhuolin Du , Xingwu Liu , Yanhan Yang , Xudong Min , Jirui Wei , Yang She , Abudushalamu Abulaiti , Xiayu Jin , Zequn Su , Shizhong Zhang , Jian Liu , Karrie M. Kiang , Gilberto Ka-Kit Leung , Xiaozheng He , Zhiyuan Zhu","doi":"10.1016/j.freeradbiomed.2026.01.016","DOIUrl":"10.1016/j.freeradbiomed.2026.01.016","url":null,"abstract":"<div><div>Mitochondrial integrity is essential for tumor cell proliferation and survival. Our previous study has demonstrated the oncogenic role of the metabolic enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in glioblastoma (GBM). Given that the non-metabolic function of certain enzymes has been reported, we aim to interrogate whether MTHFD2 has potential roles in mitochondrial integrity and dynamics, especially beyond catabolism. By using multi-faceted approaches including single-cell RNA sequencing, mt-Keima mitophagy flux assays, RNA immunoprecipitation sequencing and luciferase reporter assays, we elucidated a novel, non-canonical function of MTHFD2 in stabilizing mRNA in GBM. We found that MTHFD2 was upregulated in GBM and was enriched in specific tumor subtypes cells such as ependymal-like and OPC-like cells. Knockdown of MTHFD2 profoundly promoted mitochondrial fission that triggered excessive mitophagy and cellular apoptosis. Mechanistically, MTHFD2 directly bound to the 3′-untranslated region (3′-UTR) of TOP2A mRNA and enhanced its stability, implying the RNA binding function of this catabolic enzyme. Overexpression of TOP2A attenuated mitophagy and cellular apoptosis induced by MTHFD2 depletion, indicating a vital role of MTHFD2-TOP2A axis in modulating mitochondrial integrity. Importantly, targeting MTHFD2 impeded GBM growth in orthotopic mouse models, which could be a promising therapeutic strategy. In conclusion, we proposed a non-canonical function of MTHFD2, which bound to and stabilized the mRNA of TOP2A. Targeting MTHFD2 triggered excessive mitophagy and cell apoptosis in GBM via destabilizing TOP2A mRNA.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 93-106"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957675","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}
Pub Date : 2026-03-16Epub Date: 2026-01-23DOI: 10.1016/j.freeradbiomed.2026.01.031
Yujie Zhou , Qiangmin Qiu , Kang Xia , Bo Yu , Zhan Chen , Dalin He , Jiefu Zhu , Tianyu Wang , Tao Qiu , Jiangqiao Zhou
Renal ischemia-reperfusion injury (RIRI) is a common cause of acute kidney injury in clinical practice, frequently occurring in renal transplantation, partial nephrectomy, and cardiac surgery. Similar to phosphorylation and ubiquitination, glycation is a form of post-translational modification that is widely present in mammals. However, glycation/deglycation has not yet been investigated in the context of RIRI. To explore its regulatory role in acute-phase RIRI, we established both in vivo and in vitro renal ischemia-reperfusion models and examined the protective mechanism of the deglycating enzyme fructosamine-3-kinase (FN3K). Our results demonstrated that FN3K expression was markedly down-regulated following RIRI. FN3K over-expression alleviated renal injury in mice and cells, primarily by reducing oxidative stress and apoptosis, whereas FN3K knockdown exerted the opposite effects. Mechanistically, the protective role of FN3K was dependent on Nrf2. Specifically, FN3K promoted the nuclear translocation and antioxidant activity of Nrf2 by mediating its deglycation. In conclusion, this study is the first to reveal that FN3K confers protection against RIRI by regulating Nrf2 deglycation, thereby broadening our understanding of oxidative stress mechanisms underlying ischemia-reperfusion–induced acute kidney injury. Furthermore, these findings provide a novel theoretical basis for targeting the FN3K-Nrf2 signaling axis, and highlight a potential therapeutic target for precision intervention in acute kidney injury and the prevention of post-transplant complications.
{"title":"FN3K alleviates renal ischemia-reperfusion injury by regulating oxidative stress through Nrf2 deglycation","authors":"Yujie Zhou , Qiangmin Qiu , Kang Xia , Bo Yu , Zhan Chen , Dalin He , Jiefu Zhu , Tianyu Wang , Tao Qiu , Jiangqiao Zhou","doi":"10.1016/j.freeradbiomed.2026.01.031","DOIUrl":"10.1016/j.freeradbiomed.2026.01.031","url":null,"abstract":"<div><div>Renal ischemia-reperfusion injury (RIRI) is a common cause of acute kidney injury in clinical practice, frequently occurring in renal transplantation, partial nephrectomy, and cardiac surgery. Similar to phosphorylation and ubiquitination, glycation is a form of post-translational modification that is widely present in mammals. However, glycation/deglycation has not yet been investigated in the context of RIRI. To explore its regulatory role in acute-phase RIRI, we established both in vivo and in vitro renal ischemia-reperfusion models and examined the protective mechanism of the deglycating enzyme fructosamine-3-kinase (FN3K). Our results demonstrated that FN3K expression was markedly down-regulated following RIRI. FN3K over-expression alleviated renal injury in mice and cells, primarily by reducing oxidative stress and apoptosis, whereas FN3K knockdown exerted the opposite effects. Mechanistically, the protective role of FN3K was dependent on Nrf2. Specifically, FN3K promoted the nuclear translocation and antioxidant activity of Nrf2 by mediating its deglycation. In conclusion, this study is the first to reveal that FN3K confers protection against RIRI by regulating Nrf2 deglycation, thereby broadening our understanding of oxidative stress mechanisms underlying ischemia-reperfusion–induced acute kidney injury. Furthermore, these findings provide a novel theoretical basis for targeting the FN3K-Nrf2 signaling axis, and highlight a potential therapeutic target for precision intervention in acute kidney injury and the prevention of post-transplant complications.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 476-488"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046452","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}
Pub Date : 2026-03-16Epub Date: 2026-01-29DOI: 10.1016/j.freeradbiomed.2026.01.036
Lihui Deng , Boyang Wang , Haipeng Jie , Meitong Liu , Luyao Yu , Shuzhen Wu , Lanlan Wang , Shengnan Li , Xiaohui Hu , Yalin Yu , Guohua Song , Bo Dong
Background
Diabetic cardiomyopathy (DCM) is a major complication of diabetes mellitus, leading to significant mortality. The (Pro)renin Receptor (PRR) is implicated in cardiovascular pathology, but its specific role in regulating mitochondrial quality control and cellular senescence in the context of DCM remains poorly understood. This study aimed to elucidate the mechanism by which PRR contributes to myocardial injury in DCM.
Methods
DCM was induced in mice using a high-fat diet combined with streptozotocin injection. The function of PRR was investigated in vivo and in high-glucose (HG)-stimulated neonatal rat cardiomyocytes (NRCMs) in vitro using adenoviral vectors for overexpression and knockdown. Cardiac function, myocardial remodeling (fibrosis, hypertrophy), mitophagy, and senescence were assessed using echocardiography, histological and immunofluorescence staining, Western blot, and RT-qPCR. RNA-sequencing was employed to identify downstream targets of PRR, and the protein-protein interaction was validated by co-immunoprecipitation and pull-down assays.
Results
PRR expression was significantly upregulated in the myocardium of DCM mice and in HG-treated NRCMs. Overexpression of PRR exacerbated cardiac dysfunction, myocardial fibrosis, and hypertrophy, which was associated with impaired mitophagy and increased cellular senescence. Conversely, genetic knockdown of PRR ameliorated these pathological changes. Mechanistically, PRR was found to physically interact with and suppress kinase activity of Leucine-rich repeat kinase 2 (LRRK2). Silencing LRRK2 abolished the protective effects of PRR knockdown, confirming that LRRK2 is a critical downstream mediator of PRR's detrimental effects.
Conclusions
PRR exacerbates diabetic cardiomyopathy by suppressing LRRK2, leading to impaired mitophagy and accelerated cellular senescence. The PRR/LRRK2 axis may be a potentially promising and novel therapeutic paradigm for treating DCM, and targeting PRR may represent a possibly promising therapeutic strategy.
{"title":"(Pro)renin receptor (PRR) exacerbates diabetic cardiomyopathy by suppressing LRRK2-Mediated mitophagy and promoting senescence","authors":"Lihui Deng , Boyang Wang , Haipeng Jie , Meitong Liu , Luyao Yu , Shuzhen Wu , Lanlan Wang , Shengnan Li , Xiaohui Hu , Yalin Yu , Guohua Song , Bo Dong","doi":"10.1016/j.freeradbiomed.2026.01.036","DOIUrl":"10.1016/j.freeradbiomed.2026.01.036","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic cardiomyopathy (DCM) is a major complication of diabetes mellitus, leading to significant mortality. The (Pro)renin Receptor (PRR) is implicated in cardiovascular pathology, but its specific role in regulating mitochondrial quality control and cellular senescence in the context of DCM remains poorly understood. This study aimed to elucidate the mechanism by which PRR contributes to myocardial injury in DCM.</div></div><div><h3>Methods</h3><div>DCM was induced in mice using a high-fat diet combined with streptozotocin injection. The function of PRR was investigated in vivo and in high-glucose (HG)-stimulated neonatal rat cardiomyocytes (NRCMs) in vitro using adenoviral vectors for overexpression and knockdown. Cardiac function, myocardial remodeling (fibrosis, hypertrophy), mitophagy, and senescence were assessed using echocardiography, histological and immunofluorescence staining, Western blot, and RT-qPCR. RNA-sequencing was employed to identify downstream targets of PRR, and the protein-protein interaction was validated by co-immunoprecipitation and pull-down assays.</div></div><div><h3>Results</h3><div>PRR expression was significantly upregulated in the myocardium of DCM mice and in HG-treated NRCMs. Overexpression of PRR exacerbated cardiac dysfunction, myocardial fibrosis, and hypertrophy, which was associated with impaired mitophagy and increased cellular senescence. Conversely, genetic knockdown of PRR ameliorated these pathological changes. Mechanistically, PRR was found to physically interact with and suppress kinase activity of Leucine-rich repeat kinase 2 (LRRK2). Silencing LRRK2 abolished the protective effects of PRR knockdown, confirming that LRRK2 is a critical downstream mediator of PRR's detrimental effects.</div></div><div><h3>Conclusions</h3><div>PRR exacerbates diabetic cardiomyopathy by suppressing LRRK2, leading to impaired mitophagy and accelerated cellular senescence. The PRR/LRRK2 axis may be a potentially promising and novel therapeutic paradigm for treating DCM, and targeting PRR may represent a possibly promising therapeutic strategy.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 442-455"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074884","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}
Pub Date : 2026-03-16Epub Date: 2026-01-13DOI: 10.1016/j.freeradbiomed.2026.01.012
Weiwei Wang , Zhenghui Wang , Fujie Wang , Ying Li , Haoyang Zhou , Yanan Pu , Xufeng Chen , Yi Jiang
Background
Sepsis-induced cardiomyopathy (SICM) is one of the leading causes of mortality in sepsis patients, and currently, there are no effective treatments available. Ferroptosis has been proven to play a critical role in SICM. Exosomes from the young healthy human plasma (exosomesYoung) were shown to improve cardiac fibrosis post-myocardial infarction in our previous studies. However, their role in SICM remains unclear.
Methods
We established in vivo and in vitro models of SICM induced by lipopolysaccharide (LPS). The severity of cardiac and cardiomyocyte injury was evaluated through echocardiography, histological analysis, measurements of myocardial injury markers, and cell viability assays. Improvements in SICM via inhibition of ferroptosis by exosomesYoung were demonstrated by assessing ferroptosis-related indicators, including Fe2+, malondialdehyde (MDA), Liperfluo (LPO) levels, PTGS2 expression, and mitochondrial structural integrity.
Results
In this study, we demonstrated that exosomesYoung significantly improved cardiac function and mitigated morphological damage in the hearts of mice with SICM. ExosomesYoung also enhanced the viability of LPS-induced cardiomyocytes, reduced levels of lipid peroxides and ferroptosis biomarkers, and suppressed ROS production, mitochondrial membrane potential reduction, and mitochondrial ultrastructural damage. Mechanistically, high-throughput sequencing analysis followed by qRT-PCR validation identified miR-3130-3p as a key effector molecule. Upregulation of miR-3130-3p mimicked the therapeutic effects of exosomesYoung on LPS-induced cardiac injury and mediated the cardioprotective role of exosomesYoung against ferroptosis in SICM. Further, target gene prediction using databases and validation with a dual-luciferase reporter assay confirmed LPCAT3 as the direct target gene of miR-3130-3p in inhibiting ferroptosis. Overexpression of LPCAT3 could reverse the protective effects of miR-3130-3p on LPS-induced SICM.
Conclusions
In summary, these findings reveal for the first time that exosomesYoung improve SICM by inhibiting ferroptosis via miR-3130-3p targeting LPCAT3. This study provides novel insights into the potential of exosomesYoung as promising cardioprotective candidates for patients with SICM.
{"title":"Exosomes from young healthy human plasma ameliorate sepsis-induced cardiomyopathy by inhibiting ferroptosis via the miR-3130-3p/LPCAT3 axis","authors":"Weiwei Wang , Zhenghui Wang , Fujie Wang , Ying Li , Haoyang Zhou , Yanan Pu , Xufeng Chen , Yi Jiang","doi":"10.1016/j.freeradbiomed.2026.01.012","DOIUrl":"10.1016/j.freeradbiomed.2026.01.012","url":null,"abstract":"<div><h3>Background</h3><div>Sepsis-induced cardiomyopathy (SICM) is one of the leading causes of mortality in sepsis patients, and currently, there are no effective treatments available. Ferroptosis has been proven to play a critical role in SICM. Exosomes from the young healthy human plasma (exosomes<sup>Young</sup>) were shown to improve cardiac fibrosis post-myocardial infarction in our previous studies. However, their role in SICM remains unclear.</div></div><div><h3>Methods</h3><div>We established <em>in vivo</em> and <em>in vitro</em> models of SICM induced by lipopolysaccharide (LPS). The severity of cardiac and cardiomyocyte injury was evaluated through echocardiography, histological analysis, measurements of myocardial injury markers, and cell viability assays. Improvements in SICM <em>via</em> inhibition of ferroptosis by exosomes<sup>Young</sup> were demonstrated by assessing ferroptosis-related indicators, including Fe<sup>2+</sup>, malondialdehyde (MDA), Liperfluo (LPO) levels, PTGS2 expression, and mitochondrial structural integrity.</div></div><div><h3>Results</h3><div>In this study, we demonstrated that exosomes<sup>Young</sup> significantly improved cardiac function and mitigated morphological damage in the hearts of mice with SICM. Exosomes<sup>Young</sup> also enhanced the viability of LPS-induced cardiomyocytes, reduced levels of lipid peroxides and ferroptosis biomarkers, and suppressed ROS production, mitochondrial membrane potential reduction, and mitochondrial ultrastructural damage. Mechanistically, high-throughput sequencing analysis followed by qRT-PCR validation identified miR-3130-3p as a key effector molecule. Upregulation of miR-3130-3p mimicked the therapeutic effects of exosomes<sup>Young</sup> on LPS-induced cardiac injury and mediated the cardioprotective role of exosomes<sup>Young</sup> against ferroptosis in SICM. Further, target gene prediction using databases and validation with a dual-luciferase reporter assay confirmed LPCAT3 as the direct target gene of miR-3130-3p in inhibiting ferroptosis. Overexpression of LPCAT3 could reverse the protective effects of miR-3130-3p on LPS-induced SICM.</div></div><div><h3>Conclusions</h3><div>In summary, these findings reveal for the first time that exosomes<sup>Young</sup> improve SICM by inhibiting ferroptosis <em>via</em> miR-3130-3p targeting LPCAT3. This study provides novel insights into the potential of exosomes<sup>Young</sup> as promising cardioprotective candidates for patients with SICM.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 140-158"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976041","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}
Thyroid disorders profoundly disrupt metabolism, development, growth, pubertal timing, and fertility in domestic animals. Gonadotropin-inhibitory hormone (GnIH), a key inhibitory neuropeptide regulating reproductive function, has been implicated in metabolic dysfunction-associated infertility as well as thyroid dysfunction–related pubertal abnormalities. These observations suggest potential crosstalk between GnIH and thyroid hormones (THs), positioning GnIH as a possible integrative regulator linking the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-gonadal (HPG) axes. However, the role of GnIH in the modulation of thyroid function remains poorly defined. Using the pig as a translationally relevant model for neuroendocrine research, we investigated the peripheral effects of GnIH on TH synthesis and elucidated the underlying mechanisms in female piglets. Untargeted metabolomic analysis revealed a significant reduction in serum thyroxine levels following chronic intraperitoneal administration of GnIH compared with vehicle-treated controls. Furthermore, colocalization and pharmacological analyses demonstrated that peripheral GnIH directly suppresses TH synthesis in the thyroid gland, leading to decreased circulating TH levels and activation of the negative feedback regulation within the HPT axis. These results suggest that the thyroid gland is a primary peripheral target for GnIH-induced hypothyroidism. Subsequent in vivo and in vitro studies confirmed that peripheral GnIH disrupts mitochondrial function, inducing apoptosis and oxidative stress in thyroid follicular epithelial cells and ultimately causing hypothyroidism, while its effects on proliferation followed an opposite trend. These results establish that GnIH directly inhibits TH synthesis through mitochondrial dysfunction and follicular epithelial cell apoptosis, thereby contributing to hypothyroidism pathogenesis. Our study identifies GnIH as a novel neuroendocrine regulator of thyroid function and suggests that GnIH agonists or antagonists may offer therapeutic potential for thyroid disorders and related conditions.
{"title":"GnIH-induced mitochondrial dysfunction lead to oxidative stress and apoptosis in thyroid follicular cells, causing hypothyroidism","authors":"Ke Peng , Chengcheng Liu , Hongyu Zhu , Xingxing Song, Jiani Zhang, Bingqian Shen, Yuanyuan Xin, Wenqi Wang, Wantong Ji, Lingyuan Zhang, Meijun Lu, Guihao Tang, Junjie Ma, Jiapeng Li, Jiang Li, Yixian Wei, Jiaming Zheng, Xiaoye Wang, Chuanhuo Hu, Xun Li","doi":"10.1016/j.freeradbiomed.2026.01.032","DOIUrl":"10.1016/j.freeradbiomed.2026.01.032","url":null,"abstract":"<div><div>Thyroid disorders profoundly disrupt metabolism, development, growth, pubertal timing, and fertility in domestic animals. Gonadotropin-inhibitory hormone (GnIH), a key inhibitory neuropeptide regulating reproductive function, has been implicated in metabolic dysfunction-associated infertility as well as thyroid dysfunction–related pubertal abnormalities. These observations suggest potential crosstalk between GnIH and thyroid hormones (THs), positioning GnIH as a possible integrative regulator linking the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-gonadal (HPG) axes. However, the role of GnIH in the modulation of thyroid function remains poorly defined. Using the pig as a translationally relevant model for neuroendocrine research, we investigated the peripheral effects of GnIH on TH synthesis and elucidated the underlying mechanisms in female piglets. Untargeted metabolomic analysis revealed a significant reduction in serum thyroxine levels following chronic intraperitoneal administration of GnIH compared with vehicle-treated controls. Furthermore, colocalization and pharmacological analyses demonstrated that peripheral GnIH directly suppresses TH synthesis in the thyroid gland, leading to decreased circulating TH levels and activation of the negative feedback regulation within the HPT axis. These results suggest that the thyroid gland is a primary peripheral target for GnIH-induced hypothyroidism. Subsequent <em>in vivo</em> and <em>in vitro</em> studies confirmed that peripheral GnIH disrupts mitochondrial function, inducing apoptosis and oxidative stress in thyroid follicular epithelial cells and ultimately causing hypothyroidism, while its effects on proliferation followed an opposite trend. These results establish that GnIH directly inhibits TH synthesis through mitochondrial dysfunction and follicular epithelial cell apoptosis, thereby contributing to hypothyroidism pathogenesis. Our study identifies GnIH as a novel neuroendocrine regulator of thyroid function and suggests that GnIH agonists or antagonists may offer therapeutic potential for thyroid disorders and related conditions.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 350-367"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146029075","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}
Pub Date : 2026-03-16Epub Date: 2026-01-22DOI: 10.1016/j.freeradbiomed.2026.01.014
Zhen Zhang , Hang Han , Liyang Ding, Hong Yang, Yu Deng, Yitong Shang, Tengjiao He, Xinru Cui, Bo Xu, Xufeng Fu
Di(2-ethylhexyl) phthalate (DEHP), a widely utilized plasticizer, impairs male reproductive function; however, the precise mechanisms underlying this effect have yet to be fully elucidated. This study investigates DEHP-induced spermatocyte toxicity and identifies therapeutic strategies. Integrated network toxicology and proteomics delineated testicular toxicity mechanisms through multi-dimensional analyses. We demonstrate that DEHP exposure induces spermatocyte ferroptosis via PINK1/Parkin-mediated mitophagy. Mechanistically, the bioactive metabolite MEHP promotes NRF2 degradation through the ubiquitin-proteasome pathway, inducing excessive mitochondrial clearance. This process mediates mitochondrial Fe2+ efflux, causing iron dysregulation and lipid peroxidation. Pharmacological inhibition of mitophagy by CsA attenuated ferroptosis and restored iron homeostasis, confirming ferroptosis dependence on mitophagic activation. Crucially, NRF2 activation concurrently suppresses both mitophagic flux and ferroptotic execution. MEHP-induced NRF2 degradation initiates pathological mitophagy and facilitates mitochondrial iron efflux, resulting in dysregulated iron metabolism within spermatocytes. This cascade culminates in spermatocyte ferroptosis mediated by Fe2+ accumulation and lipid peroxidation. This work provides definitive evidence linking environmental toxicant-induced mitophagy to germ cell ferroptosis, identifies NRF2 as a central regulator of this pathway, and proposes targeted mitophagy inhibition combined with NRF2 stabilization as therapeutic interventions.
{"title":"Di(2-ethylhexyl) phthalate induces male reproductive toxicity through mitophagy-dependent ferroptosis of spermatocytes in mice","authors":"Zhen Zhang , Hang Han , Liyang Ding, Hong Yang, Yu Deng, Yitong Shang, Tengjiao He, Xinru Cui, Bo Xu, Xufeng Fu","doi":"10.1016/j.freeradbiomed.2026.01.014","DOIUrl":"10.1016/j.freeradbiomed.2026.01.014","url":null,"abstract":"<div><div>Di(2-ethylhexyl) phthalate (DEHP), a widely utilized plasticizer, impairs male reproductive function; however, the precise mechanisms underlying this effect have yet to be fully elucidated. This study investigates DEHP-induced spermatocyte toxicity and identifies therapeutic strategies. Integrated network toxicology and proteomics delineated testicular toxicity mechanisms through multi-dimensional analyses. We demonstrate that DEHP exposure induces spermatocyte ferroptosis via PINK1/Parkin-mediated mitophagy. Mechanistically, the bioactive metabolite MEHP promotes NRF2 degradation through the ubiquitin-proteasome pathway, inducing excessive mitochondrial clearance. This process mediates mitochondrial Fe<sup>2+</sup> efflux, causing iron dysregulation and lipid peroxidation. Pharmacological inhibition of mitophagy by CsA attenuated ferroptosis and restored iron homeostasis, confirming ferroptosis dependence on mitophagic activation. Crucially, NRF2 activation concurrently suppresses both mitophagic flux and ferroptotic execution. MEHP-induced NRF2 degradation initiates pathological mitophagy and facilitates mitochondrial iron efflux, resulting in dysregulated iron metabolism within spermatocytes. This cascade culminates in spermatocyte ferroptosis mediated by Fe<sup>2+</sup> accumulation and lipid peroxidation. This work provides definitive evidence linking environmental toxicant-induced mitophagy to germ cell ferroptosis, identifies NRF2 as a central regulator of this pathway, and proposes targeted mitophagy inhibition combined with NRF2 stabilization as therapeutic interventions.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 252-268"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024671","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}
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