Preeclampsia (PE) is a pregnancy disorder characterized by placental maladaptation and maternal hypertension, with oxidative stress and lipid peroxidation as central features. Here we identify 2,4-dienoyl-CoA reductase 1 (DECR1), the rate-limiting enzyme in the auxiliary β-oxidation of unsaturated fatty acids, as a key regulator of trophoblast lipid redox balance. DECR1 expression is reduced in placentas from patients with late-onset preeclampsia (LOPE) and an L-NAME-induced PE mouse models. Genetic or pharmacological inhibition of DECR1 increases PUFA-rich lipid accumulation, enhances lipid peroxidation, and induces mitochondrial dysfunction, leading to loss of membrane potential, reactive oxygen species buildup, ATP depletion, and impaired trophoblast migration and invasion. In vivo, DECR1 inhibition causes hypertension, renal injury, fetal growth restriction, and defective placental vascular remodeling. Mechanistically, DECR1 loss disrupts mitochondrial quality control by suppressing mitocytosis, effects that are reversed by radical-trapping agents or mitochondria-targeted antioxidants. Liproxstatin-1 treatment restores maternal, fetal, and placental homeostasis. These findings define a DECR1-lipid peroxidation-mitochondria axis that maintains trophoblast function and placental adaptation, highlighting DECR1 as a potential therapeutic target for PE.
{"title":"DECR1 deficiency activates a lipid peroxidation-mitocytosis-mitochondrial dysfunction axis in trophoblasts to promote preeclampsia.","authors":"Qin Zhang, Huilian Feng, Ruixin Chen, Yao Long, Wei Chu, Yiran Li, Wei Dai, Qi Yao, Xin Luo, Hui Li, Hongbo Qi","doi":"10.1016/j.freeradbiomed.2026.03.049","DOIUrl":"10.1016/j.freeradbiomed.2026.03.049","url":null,"abstract":"<p><p>Preeclampsia (PE) is a pregnancy disorder characterized by placental maladaptation and maternal hypertension, with oxidative stress and lipid peroxidation as central features. Here we identify 2,4-dienoyl-CoA reductase 1 (DECR1), the rate-limiting enzyme in the auxiliary β-oxidation of unsaturated fatty acids, as a key regulator of trophoblast lipid redox balance. DECR1 expression is reduced in placentas from patients with late-onset preeclampsia (LOPE) and an L-NAME-induced PE mouse models. Genetic or pharmacological inhibition of DECR1 increases PUFA-rich lipid accumulation, enhances lipid peroxidation, and induces mitochondrial dysfunction, leading to loss of membrane potential, reactive oxygen species buildup, ATP depletion, and impaired trophoblast migration and invasion. In vivo, DECR1 inhibition causes hypertension, renal injury, fetal growth restriction, and defective placental vascular remodeling. Mechanistically, DECR1 loss disrupts mitochondrial quality control by suppressing mitocytosis, effects that are reversed by radical-trapping agents or mitochondria-targeted antioxidants. Liproxstatin-1 treatment restores maternal, fetal, and placental homeostasis. These findings define a DECR1-lipid peroxidation-mitochondria axis that maintains trophoblast function and placental adaptation, highlighting DECR1 as a potential therapeutic target for PE.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"1-15"},"PeriodicalIF":8.2,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147491045","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 : 2026-03-17DOI: 10.1016/j.freeradbiomed.2026.03.045
Cristina Maroto-Serrat, Francisco Sanus, Albert Caballeria, Shuozhou Liang, Jordi Gracia-Sancho, Araní Casillas-Ramírez, Carmen Peralta
Donor shortage has increased liver transplantation (LT) waiting lists. The use of livers grafts from extended criteria donors (ECD), including deceased donors with alcoholic liver disease (ALD) or severe steatosis, particularly after prolonged cold ischemia (CI), is associated with a risk of graft dysfunction and reduced post-liver transplantation outcomes. This study investigated whether hepatic NPY depletion in donors after brain death (DBD) and donors after cardiocirculatory death (DCD) contributes to liver injury and regenerative failure. Rat models of donors after brain death (DBDs) or cardiocirculatory death (DCDs) with ALD or severe steatosis were used to assess how hepatic sympathetic nervous system (SNS) modulation, adrenal medulla (AM) removal, NPY (alone or with norepinephrine, NE), and AMPK-NO signalling affect liver damage and regeneration before retrieval from donors and after 24 h CI followed by ex vivo reperfusion or transplantation. In DBDs, SNS-derived hepatic NPY decreased, while NE was preserved thanks to AM. In DCDs, both NPY and NE (derived from SNS) were depleted. NPY administration (but not SNS stimulation) restored hepatic NPY and protected DBD grafts against damage and regenerative failure. In DCDs, only combined NPY+NE or SNS stimulation restored both NPY and NE, reducing damage but not improving regeneration. Protection in both donor types depended on AMPK-NO signalling, which was reduced before retrieval and restored by NPY (DBDs), NPY+NE or SNS stimulation (DCDs). Protection depended on AMPK-NO signaling and persisted after CI and reperfusion, improving survival. In contrast, AMPK activator, AICAR-which increased NO- and NO supplementation caused excessive NO after CI and reperfusion, increasing peroxynitrite generation, oxidative stress, liver damage and regenerative failure. The donor-type-specific drugs/interventions (NPY in DCDs; NPY+NE or ES stimulation in DCDs) might improve clinical LT outcomes from extended-criteria donors, whereas AICAR or NO supplementation is detrimental.
{"title":"THE ROLE OF NPY IN LIVER TRANSPLANTATION FROM EXTENDED-CRITERIA DONORS.","authors":"Cristina Maroto-Serrat, Francisco Sanus, Albert Caballeria, Shuozhou Liang, Jordi Gracia-Sancho, Araní Casillas-Ramírez, Carmen Peralta","doi":"10.1016/j.freeradbiomed.2026.03.045","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.03.045","url":null,"abstract":"<p><p>Donor shortage has increased liver transplantation (LT) waiting lists. The use of livers grafts from extended criteria donors (ECD), including deceased donors with alcoholic liver disease (ALD) or severe steatosis, particularly after prolonged cold ischemia (CI), is associated with a risk of graft dysfunction and reduced post-liver transplantation outcomes. This study investigated whether hepatic NPY depletion in donors after brain death (DBD) and donors after cardiocirculatory death (DCD) contributes to liver injury and regenerative failure. Rat models of donors after brain death (DBDs) or cardiocirculatory death (DCDs) with ALD or severe steatosis were used to assess how hepatic sympathetic nervous system (SNS) modulation, adrenal medulla (AM) removal, NPY (alone or with norepinephrine, NE), and AMPK-NO signalling affect liver damage and regeneration before retrieval from donors and after 24 h CI followed by ex vivo reperfusion or transplantation. In DBDs, SNS-derived hepatic NPY decreased, while NE was preserved thanks to AM. In DCDs, both NPY and NE (derived from SNS) were depleted. NPY administration (but not SNS stimulation) restored hepatic NPY and protected DBD grafts against damage and regenerative failure. In DCDs, only combined NPY+NE or SNS stimulation restored both NPY and NE, reducing damage but not improving regeneration. Protection in both donor types depended on AMPK-NO signalling, which was reduced before retrieval and restored by NPY (DBDs), NPY+NE or SNS stimulation (DCDs). Protection depended on AMPK-NO signaling and persisted after CI and reperfusion, improving survival. In contrast, AMPK activator, AICAR-which increased NO- and NO supplementation caused excessive NO after CI and reperfusion, increasing peroxynitrite generation, oxidative stress, liver damage and regenerative failure. The donor-type-specific drugs/interventions (NPY in DCDs; NPY+NE or ES stimulation in DCDs) might improve clinical LT outcomes from extended-criteria donors, whereas AICAR or NO supplementation is detrimental.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147485041","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.2026.01.017
Xinli Hu , Haojie Zhang , Zheng Wang , Xuan Zhao , Tao Hu , Chengxin Liu , Xiaolong Chen , Wei Wang , Shibao Lu
Osteoporosis is driven in large part by excessive osteoclast-mediated bone resorption, and exercise-induced myokines such as irisin have emerged as potential modulators of bone remodeling, yet the mechanism by which irisin regulates osteoclastogenesis remains incompletely defined. Here, we integrated clinical analyses, mechanistic cell studies, and ovariectomized (OVX) mouse models to determine whether irisin protects against estrogen deficiency–induced bone loss and to delineate the underlying signaling axis. In 109 postmenopausal women, circulating irisin levels were positively associated with bone mineral density and inversely correlated with the bone resorption marker β-CTX. In vitro, irisin dose-dependently suppressed RANKL-induced osteoclast differentiation, F-actin ring formation, and resorption activity in bone marrow–derived macrophages, accompanied by downregulation of osteoclast marker genes and proteins. Mechanistically, network pharmacology and molecular docking, together with CETSA, co-immunoprecipitation, and immunofluorescence, supported a direct irisin–Nrf2 interaction; irisin stabilized Nrf2 and thereby restrained TRAF6-mediated K63-linked ubiquitination and activation of STING, resulting in attenuation of downstream NF-κB signaling. In vivo, irisin administration improved trabecular microarchitecture and reduced osteoclast number/activity in OVX mice, whereas these protective effects were largely abolished in Nrf2-deficient mice, indicating an Nrf2-dependent mechanism. Collectively, our findings identify an Irisin–Nrf2–STING/NF-κB axis that suppresses osteoclastogenesis and mitigates estrogen deficiency–induced bone loss, supporting irisin as a promising therapeutic candidate for osteoporosis.
{"title":"Exercise-derived irisin prevents bone loss via Nrf2 activation and inhibition of STING/NF-κB signaling","authors":"Xinli Hu , Haojie Zhang , Zheng Wang , Xuan Zhao , Tao Hu , Chengxin Liu , Xiaolong Chen , Wei Wang , Shibao Lu","doi":"10.1016/j.freeradbiomed.2026.01.017","DOIUrl":"10.1016/j.freeradbiomed.2026.01.017","url":null,"abstract":"<div><div>Osteoporosis is driven in large part by excessive osteoclast-mediated bone resorption, and exercise-induced myokines such as irisin have emerged as potential modulators of bone remodeling, yet the mechanism by which irisin regulates osteoclastogenesis remains incompletely defined. Here, we integrated clinical analyses, mechanistic cell studies, and ovariectomized (OVX) mouse models to determine whether irisin protects against estrogen deficiency–induced bone loss and to delineate the underlying signaling axis. In 109 postmenopausal women, circulating irisin levels were positively associated with bone mineral density and inversely correlated with the bone resorption marker β-CTX. In vitro, irisin dose-dependently suppressed RANKL-induced osteoclast differentiation, F-actin ring formation, and resorption activity in bone marrow–derived macrophages, accompanied by downregulation of osteoclast marker genes and proteins. Mechanistically, network pharmacology and molecular docking, together with CETSA, co-immunoprecipitation, and immunofluorescence, supported a direct irisin–Nrf2 interaction; irisin stabilized Nrf2 and thereby restrained TRAF6-mediated K63-linked ubiquitination and activation of STING, resulting in attenuation of downstream NF-κB signaling. In vivo, irisin administration improved trabecular microarchitecture and reduced osteoclast number/activity in OVX mice, whereas these protective effects were largely abolished in Nrf2-deficient mice, indicating an Nrf2-dependent mechanism. Collectively, our findings identify an Irisin–Nrf2–STING/NF-κB axis that suppresses osteoclastogenesis and mitigates estrogen deficiency–induced bone loss, supporting irisin as a promising therapeutic candidate for osteoporosis.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 51-68"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957700","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.2026.01.015
Yixiao Xu , Yishun Gong , Jiafa Zhong , Jiucun Wang , Binghong Gao
Objective
Active heat acclimation is widely used by athletes or workers exposed to heat, yet its impact on skeletal muscle mitochondrial function and the underlying molecular regulators remain incompletely understood. This study aimed to investigate how active heat acclimation improves skeletal muscle mitochondrial function, with a specific focus on transient receptor potential vanilloid 1 (TRPV1) as an important mediator.
Methods
A 4-week intervention was conducted in trained runners (exercise in heat vs. thermoneutral conditions) and in mice exposed to heat, exercise, TRPV1 activation (nonivamide), or TRPV1 inhibition (AMG9810). Aerobic performance, substrate utilization, mitochondrial respiration, H2O2 emission, mitochondrial ultrastructure, and molecular markers of biogenesis and mitophagy were assessed.
Results
In humans, active heat acclimation improved ventilatory thresholds, enhanced lactate clearance, and reduced carbohydrate oxidation during submaximal exercise. In mice, active heat acclimation increased mitochondrial biogenesis (PGC-1α, p-p38 MAPK, TFAM), enhanced mitophagy (Pink1, Parkin), improved OXPHOS and ETS capacities, and elevated TRPV1 expression. Pharmacological TRPV1 activation augmented mitochondrial remodeling and improved exercise performance. Conversely, TRPV1 inhibition blunted heat-induced mitochondrial biogenesis, mitophagy activation, and structural remodeling.
Conclusion
TRPV1 is an important mediator of mitochondrial adaptations to active heat acclimation, promoting mitochondrial turnover and enhancing respiratory capacity, thereby supporting the improvement of aerobic capacity.
{"title":"TRPV1 activation by active heat acclimation drives skeletal muscle mitochondrial turnover","authors":"Yixiao Xu , Yishun Gong , Jiafa Zhong , Jiucun Wang , Binghong Gao","doi":"10.1016/j.freeradbiomed.2026.01.015","DOIUrl":"10.1016/j.freeradbiomed.2026.01.015","url":null,"abstract":"<div><h3>Objective</h3><div>Active heat acclimation is widely used by athletes or workers exposed to heat, yet its impact on skeletal muscle mitochondrial function and the underlying molecular regulators remain incompletely understood. This study aimed to investigate how active heat acclimation improves skeletal muscle mitochondrial function, with a specific focus on transient receptor potential vanilloid 1 (TRPV1) as an important mediator.</div></div><div><h3>Methods</h3><div>A 4-week intervention was conducted in trained runners (exercise in heat vs. thermoneutral conditions) and in mice exposed to heat, exercise, TRPV1 activation (nonivamide), or TRPV1 inhibition (AMG9810). Aerobic performance, substrate utilization, mitochondrial respiration, H<sub>2</sub>O<sub>2</sub> emission, mitochondrial ultrastructure, and molecular markers of biogenesis and mitophagy were assessed.</div></div><div><h3>Results</h3><div>In humans, active heat acclimation improved ventilatory thresholds, enhanced lactate clearance, and reduced carbohydrate oxidation during submaximal exercise. In mice, active heat acclimation increased mitochondrial biogenesis (PGC-1α, p-p38 MAPK, TFAM), enhanced mitophagy (Pink1, Parkin), improved OXPHOS and ETS capacities, and elevated TRPV1 expression. Pharmacological TRPV1 activation augmented mitochondrial remodeling and improved exercise performance. Conversely, TRPV1 inhibition blunted heat-induced mitochondrial biogenesis, mitophagy activation, and structural remodeling.</div></div><div><h3>Conclusion</h3><div>TRPV1 is an important mediator of mitochondrial adaptations to active heat acclimation, promoting mitochondrial turnover and enhancing respiratory capacity, thereby supporting the improvement of aerobic capacity.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 368-380"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951799","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: 2026-01-19DOI: 10.1016/j.freeradbiomed.2026.01.027
Hao Xu , Jingyi Yang , Yu Zhang , Shihui Li , Ziwei Wang , Xiaojin Li , Mixia Cao , Erhui Jin , Shenghe Li , Chang Liu , Lei Li
Cadmium (Cd), a pervasive environmental toxicant, induces hepatotoxicity via mitochondrial damage and dysregulated inflammation. Astragaloside IV (AS-IV), the primary bioactive constituent of Astragalus membranaceus with antioxidative/anti-inflammatory properties, has an undefined regulatory role in the cGAS-STING axis during Cd-induced hepatic injury. In this study, the cytoprotective mechanisms of AS-IV against Cd-induced hepatotoxicity were investigated. The results showed that Cd exposure significantly impaired hepatocellular viability, induced mitochondrial dysfunction, promoted mitochondrial DNA (mtDNA) release into the cytosol, and thereby activated the cGAS-STING signaling pathway, while AS-IV intervention effectively mitigated Cd-induced mitochondrial perturbations, suppressed mtDNA efflux, and inhibited cGAS-STING pathway activation by attenuating mtDNA-dependent STING activation via suppressing cytosolic mtDNA release.
Collectively, AS-IV exerts robust hepatoprotection against Cd toxicity via preservation of mitochondrial integrity, inhibition of cytosolic mtDNA translocation, and suppression of cGAS-STING-driven innate immune hyperactivation. These findings nominate AS-IV as a viable therapeutic countermeasure against heavy metal-induced organ damage.
镉（Cd）是一种普遍存在的环境毒物，通过线粒体损伤和炎症失调引起肝毒性。黄芪甲苷（Astragaloside IV, AS-IV）是黄芪的主要生物活性成分，具有抗氧化/抗炎作用，在cd诱导的肝损伤过程中对cGAS-STING轴的调节作用尚未明确。本研究探讨了AS-IV对cd诱导的肝毒性的细胞保护机制。结果表明，Cd暴露显著损害肝细胞活力，诱导线粒体功能障碍，促进线粒体DNA （mtDNA）释放到细胞质中，从而激活cGAS-STING信号通路，而AS-IV干预通过抑制细胞质mtDNA释放来减弱mtDNA依赖性的STING激活，从而有效减轻Cd诱导的线粒体扰动，抑制mtDNA外泄，抑制cGAS-STING通路激活。总的来说，AS-IV通过保存线粒体完整性、抑制细胞质mtDNA易位和抑制cgas - sting驱动的先天免疫过度激活，对Cd毒性具有强大的肝保护作用。这些发现表明as - iv是一种可行的治疗重金属引起的器官损伤的对策。
{"title":"Targeting mitochondrial permeability and cytosolic mtDNA release: Astragaloside IV suppresses cGAS-STING signaling pathway to protect against cadmium-induced hepatotoxicity","authors":"Hao Xu , Jingyi Yang , Yu Zhang , Shihui Li , Ziwei Wang , Xiaojin Li , Mixia Cao , Erhui Jin , Shenghe Li , Chang Liu , Lei Li","doi":"10.1016/j.freeradbiomed.2026.01.027","DOIUrl":"10.1016/j.freeradbiomed.2026.01.027","url":null,"abstract":"<div><div>Cadmium (Cd), a pervasive environmental toxicant, induces hepatotoxicity via mitochondrial damage and dysregulated inflammation. Astragaloside IV (AS-IV), the primary bioactive constituent of <em>Astragalus membranaceus</em> with antioxidative/anti-inflammatory properties, has an undefined regulatory role in the cGAS-STING axis during Cd-induced hepatic injury. In this study, the cytoprotective mechanisms of AS-IV against Cd-induced hepatotoxicity were investigated. The results showed that Cd exposure significantly impaired hepatocellular viability, induced mitochondrial dysfunction, promoted mitochondrial DNA (mtDNA) release into the cytosol, and thereby activated the cGAS-STING signaling pathway, while AS-IV intervention effectively mitigated Cd-induced mitochondrial perturbations, suppressed mtDNA efflux, and inhibited cGAS-STING pathway activation by attenuating mtDNA-dependent STING activation via suppressing cytosolic mtDNA release.</div><div>Collectively, AS-IV exerts robust hepatoprotection against Cd toxicity via preservation of mitochondrial integrity, inhibition of cytosolic mtDNA translocation, and suppression of cGAS-STING-driven innate immune hyperactivation. These findings nominate AS-IV as a viable therapeutic countermeasure against heavy metal-induced organ damage.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 239-251"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017810","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: 2026-01-27DOI: 10.1016/j.freeradbiomed.2026.01.028
Jiacong Mo , Yu Jiang , Fan Zhang , Congyu Zhang , Dandan Qiu , Wanyue Huang , Yi Ren , Lixia Yuan , Ruiai Chen
Porcine epidemic diarrhea virus (PEDV) causes severe diarrhea and high mortality in neonatal piglets, largely due to oxidative stress–induced epithelial injury. However, the molecular mechanisms by which viral and host factors regulate redox homeostasis during PEDV infection remain unclear. In this in vitro study, we used IPEC-J2, LLC-PK1, and HEK293T cells to demonstrate that PEDV disrupted intracellular redox balance by suppressing glutathione biosynthesis through inhibition of the glutathione synthetase (GSS) and glutamate–cysteine ligase (GCL). Increasing GSH levels suppressed PEDV replication, whereas blocking GSH synthesis enhanced viral replication. We further found that PEDV impaired the Nuclear factor erythroid 2-related factor 2 (NRF2)/Heme Oxygenase-1 (HO-1) antioxidant signaling pathway. NRF2 overexpression or pharmacological activation inhibited PEDV replication, whereas NRF2 knockdown promoted viral replication. Screening of PEDV-encoded proteins identified Non-structural protein 1 and 2 (NSP1) and Non-structural protein 2 (NSP2) as viral factors that destabilized NRF2 through proteasomal degradation. Mechanistically, NSP1 and NSP2 interacted with the double glycine repeat (DGR) domain of Kelch-like ECH-associated protein 1 (KEAP1), strengthening KEAP1-NRF2 binding. NSP1 reduced K63-linked ubiquitination of NRF2, while NSP2 enhanced its K48-linked ubiquitination, thereby cooperatively accelerating NRF2 degradation. In summary, this study identified a previously unrecognized mechanism by which PEDV induces oxidative stress through coordinated viral modulation of the GSS and GCL and NRF2/HO-1 pathways. These findings highlight key redox-regulatory nodes that may serve as promising targets for antiviral drug and vaccine development.
{"title":"Distinct viral strategies of Porcine Epidemic Diarrhea Virus NSP1 and NSP2 converge on KEAP1 to degrade NRF2 and suppress host antioxidant defense","authors":"Jiacong Mo , Yu Jiang , Fan Zhang , Congyu Zhang , Dandan Qiu , Wanyue Huang , Yi Ren , Lixia Yuan , Ruiai Chen","doi":"10.1016/j.freeradbiomed.2026.01.028","DOIUrl":"10.1016/j.freeradbiomed.2026.01.028","url":null,"abstract":"<div><div>Porcine epidemic diarrhea virus (<strong>PEDV</strong>) causes severe diarrhea and high mortality in neonatal piglets, largely due to oxidative stress–induced epithelial injury. However, the molecular mechanisms by which viral and host factors regulate redox homeostasis during PEDV infection remain unclear. In this in vitro study, we used IPEC-J2, LLC-PK1, and HEK293T cells to demonstrate that PEDV disrupted intracellular redox balance by suppressing glutathione biosynthesis through inhibition of the glutathione synthetase (<strong>GSS</strong>) and glutamate–cysteine ligase (<strong>GCL</strong>). Increasing GSH levels suppressed PEDV replication, whereas blocking GSH synthesis enhanced viral replication. We further found that PEDV impaired the Nuclear factor erythroid 2-related factor 2 (<strong>NRF2</strong>)/Heme Oxygenase-1 (<strong>HO-1</strong>) antioxidant signaling pathway. NRF2 overexpression or pharmacological activation inhibited PEDV replication, whereas NRF2 knockdown promoted viral replication. Screening of PEDV-encoded proteins identified Non-structural protein 1 and 2 (<strong>NSP1</strong>) and Non-structural protein 2 (<strong>NSP2</strong>) as viral factors that destabilized NRF2 through proteasomal degradation. Mechanistically, NSP1 and NSP2 interacted with the double glycine repeat (<strong>DGR</strong>) domain of Kelch-like ECH-associated protein 1 (<strong>KEAP1</strong>), strengthening KEAP1-NRF2 binding. NSP1 reduced K63-linked ubiquitination of NRF2, while NSP2 enhanced its K48-linked ubiquitination, thereby cooperatively accelerating NRF2 degradation. In summary, this study identified a previously unrecognized mechanism by which PEDV induces oxidative stress through coordinated viral modulation of the GSS and GCL and NRF2/HO-1 pathways. These findings highlight key redox-regulatory nodes that may serve as promising targets for antiviral drug and vaccine development.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 531-546"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146085150","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.2025.12.059
Ying Liu , Chulong Fang , Changling Chen , Yuhang Yu , Jifen Wang , Lan Ye , Chunlin Zhang , Zhanhui Feng
<div><h3>Objective</h3><div>Beyond neuroinflammation, oxidative stress is a key pathomechanism in epilepsy. This study investigated a novel SGLT2/NHE-1/NLRP3 signaling axis and evaluated its role in driving oxidative stress and neuroinflammation in epilepsy. We aimed to determine whether targeted inhibition of this axis could alleviate neuronal excitability and cognitive deficits by restoring redox balance and suppressing neuroinflammation.</div></div><div><h3>Methods</h3><div>Network pharmacology predicted the primary anti-epileptic target of dapagliflozin. Bioinformatic analysis was performed on the GEO dataset GSE256068 from patients with temporal lobe epilepsy. A PTZ-kindled mouse model was established and treated with dapagliflozin (SGLT2 inhibitor), cariporide (NHE-1 inhibitor), or CY09 (NLRP3 inhibitor). Seizure behavior and EEG were recorded; cognitive function was assessed using the Morris water maze. Molecular analyses (RT-qPCR, Western blot, immunohistochemistry, ELISA, etc.) were conducted to evaluate neuroinflammation and oxidative stress. Complementary in vitro studies used HT22 hippocampal neuronal cells (a glia-free model) to validate the neuron-intrinsic operation of axis's role; Targeted inhibition of each component was performed using specific inhibitors, and molecular interactions were interrogated through overexpression, functional rescue experiments, molecular docking, and co-immunoprecipitation.</div></div><div><h3>Results</h3><div>Bioinformatic and molecular analyses confirmed concerted upregulation of SGLT2, NHE-1, and NLRP3 in epileptic human and mouse hippocampi (p < 0.01), with significant enrichment in NOD-like receptor signaling pathway. All three inhibitors not only reduced seizure severity included seizure scores (mean seizure grade decreased from 4.88 to 3.12–3.48, <em>p</em> < 0.01), abnormal EEG discharges, and seizure duration (mean duration decreased from 42.32 min to 5.33–9.77 min, <em>p</em> < 0.01), but aslo improved spatial learning and memory abilities. In addition, inhibition of SGLT2/NHE-1/NLRP3 signaling axis mitigated oxidative damage by reducing ROS production and lipid peroxidation, while enhancing antioxidant defense (<em>p</em> < 0.05). Crucially, they suppressed NLRP3 inflammasome activation and neuroinflammation. In vitro studies defined a core unidirectional SGLT2→NHE-1→NLRP3 cascade functioning within neurons and revealed its operation within a self-amplifying regulatory network, demonstrating that inhibition at any node effectively attenuated both LPS-induced oxidative stress and inflammatory responses in the absence of glial cells. Direct protein interactions within the axis were identified, supporting the formation of a functional signaling complex. This integrated model positions oxidative stress as both a trigger and a sustained component coupled with neuroinflammation in a feed-forward loop.</div></div><div><h3>Conclusion</h3><div>Our findings unveil the SGLT2/NHE-1/NLRP3 axi
{"title":"Inhibition of the SGLT2/NHE-1/NLRP3 signaling axis attenuates neuroinflammation and oxidative stress to ameliorate seizures and cognitive impairment in epileptic mice","authors":"Ying Liu , Chulong Fang , Changling Chen , Yuhang Yu , Jifen Wang , Lan Ye , Chunlin Zhang , Zhanhui Feng","doi":"10.1016/j.freeradbiomed.2025.12.059","DOIUrl":"10.1016/j.freeradbiomed.2025.12.059","url":null,"abstract":"<div><h3>Objective</h3><div>Beyond neuroinflammation, oxidative stress is a key pathomechanism in epilepsy. This study investigated a novel SGLT2/NHE-1/NLRP3 signaling axis and evaluated its role in driving oxidative stress and neuroinflammation in epilepsy. We aimed to determine whether targeted inhibition of this axis could alleviate neuronal excitability and cognitive deficits by restoring redox balance and suppressing neuroinflammation.</div></div><div><h3>Methods</h3><div>Network pharmacology predicted the primary anti-epileptic target of dapagliflozin. Bioinformatic analysis was performed on the GEO dataset GSE256068 from patients with temporal lobe epilepsy. A PTZ-kindled mouse model was established and treated with dapagliflozin (SGLT2 inhibitor), cariporide (NHE-1 inhibitor), or CY09 (NLRP3 inhibitor). Seizure behavior and EEG were recorded; cognitive function was assessed using the Morris water maze. Molecular analyses (RT-qPCR, Western blot, immunohistochemistry, ELISA, etc.) were conducted to evaluate neuroinflammation and oxidative stress. Complementary in vitro studies used HT22 hippocampal neuronal cells (a glia-free model) to validate the neuron-intrinsic operation of axis's role; Targeted inhibition of each component was performed using specific inhibitors, and molecular interactions were interrogated through overexpression, functional rescue experiments, molecular docking, and co-immunoprecipitation.</div></div><div><h3>Results</h3><div>Bioinformatic and molecular analyses confirmed concerted upregulation of SGLT2, NHE-1, and NLRP3 in epileptic human and mouse hippocampi (p < 0.01), with significant enrichment in NOD-like receptor signaling pathway. All three inhibitors not only reduced seizure severity included seizure scores (mean seizure grade decreased from 4.88 to 3.12–3.48, <em>p</em> < 0.01), abnormal EEG discharges, and seizure duration (mean duration decreased from 42.32 min to 5.33–9.77 min, <em>p</em> < 0.01), but aslo improved spatial learning and memory abilities. In addition, inhibition of SGLT2/NHE-1/NLRP3 signaling axis mitigated oxidative damage by reducing ROS production and lipid peroxidation, while enhancing antioxidant defense (<em>p</em> < 0.05). Crucially, they suppressed NLRP3 inflammasome activation and neuroinflammation. In vitro studies defined a core unidirectional SGLT2→NHE-1→NLRP3 cascade functioning within neurons and revealed its operation within a self-amplifying regulatory network, demonstrating that inhibition at any node effectively attenuated both LPS-induced oxidative stress and inflammatory responses in the absence of glial cells. Direct protein interactions within the axis were identified, supporting the formation of a functional signaling complex. This integrated model positions oxidative stress as both a trigger and a sustained component coupled with neuroinflammation in a feed-forward loop.</div></div><div><h3>Conclusion</h3><div>Our findings unveil the SGLT2/NHE-1/NLRP3 axi","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 742-759"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044010","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.2026.01.053
Yingqi Xu , Junyu Li , Shanshan Ma , Ting Yang , Ziyue Shen , Mingtao Li , Qiaoying Huang
Extrusion of damaged mitochondria is emerging as a trigger of innate immune activation. Parkinson's disease (PD), characterized by profound mitochondrial dysfunction, may involve similar mechanisms. Here, we report that dopaminergic neurons release damaged mitochondria into the extracellular space in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. These neuron-derived mitochondria were subsequently engulfed by glial cells, eliciting robust inflammatory responses. Autophagy inhibition did not affect mitochondrial release, indicating a non-canonical extrusion pathway. Upon mitochondrial damage, Rab27a and Rab27b translocated to the outer mitochondrial membrane, mediating mitochondrial export from dopaminergic neurons. Conditional Rab27 knockdown in dopaminergic neurons reduced extracellular mitochondrial accumulation, microglial activation, antiviral signaling, and dopaminergic neurodegeneration. Together, these findings identify Rab27-dependent mitochondrial extrusion as a critical mechanism coupling dopaminergic neuronal injury to neuroinflammation and neurodegeneration in PD.
{"title":"Rab27-dependent mitochondrial extrusion from dopaminergic neurons drives neuroinflammation and neurodegeneration in the MPTP mouse model of Parkinson's disease","authors":"Yingqi Xu , Junyu Li , Shanshan Ma , Ting Yang , Ziyue Shen , Mingtao Li , Qiaoying Huang","doi":"10.1016/j.freeradbiomed.2026.01.053","DOIUrl":"10.1016/j.freeradbiomed.2026.01.053","url":null,"abstract":"<div><div>Extrusion of damaged mitochondria is emerging as a trigger of innate immune activation. Parkinson's disease (PD), characterized by profound mitochondrial dysfunction, may involve similar mechanisms. Here, we report that dopaminergic neurons release damaged mitochondria into the extracellular space in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. These neuron-derived mitochondria were subsequently engulfed by glial cells, eliciting robust inflammatory responses. Autophagy inhibition did not affect mitochondrial release, indicating a non-canonical extrusion pathway. Upon mitochondrial damage, Rab27a and Rab27b translocated to the outer mitochondrial membrane, mediating mitochondrial export from dopaminergic neurons. Conditional <em>Rab27</em> knockdown in dopaminergic neurons reduced extracellular mitochondrial accumulation, microglial activation, antiviral signaling, and dopaminergic neurodegeneration. Together, these findings identify Rab27-dependent mitochondrial extrusion as a critical mechanism coupling dopaminergic neuronal injury to neuroinflammation and neurodegeneration in PD.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 780-795"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096920","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: 2026-01-16DOI: 10.1016/j.freeradbiomed.2026.01.024
Yang Yu , Zhangyu Liu , Jiayu Huang , Xun Qin , Xi Chen , Huiling Nie , Jin Yao , Juxue Li , Qin Jiang
Background
Pathological ocular neovascularization is closely linked to aberrant histone modifications, yet the underlying molecular mechanisms remain incompletely defined. This study investigates the role of the histone demethylase JMJD1C and its encoding gene Jmjd1c in driving pathological angiogenesis and evaluates its therapeutic potential in ocular proliferative vascular diseases.
Methods
Jmjd1c expression was examined in mouse models of ocular neovascularization and in endothelial cells (ECs) using immunostaining, qRT-PCR, and Western blotting. The pro-angiogenic functions of JMJD1C were assessed through EdU incorporation, Transwell migration, tube-formation, and spheroid-sprouting assays in vitro, as well as retinal flat-mount isolectin-B4 staining and H&E staining in vivo. RNA sequencing, immunostaining, qPCR, Western blotting, and ChIP-qPCR were employed to dissect the molecular mechanisms by which JMJD1C regulates pathological angiogenesis.
Results
Endothelial-specific deletion of Jmjd1c markedly reduced pathological neovascularization in both oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) models. Loss of JMJD1C impaired endothelial cell proliferation, migration, tube formation, and sprouting angiogenesis. Mechanistically, Jmjd1c deletion suppressed Srebf2 transcription and cholesterol biosynthesis by increasing repressive H3K9me2 histone marks in endothelial cells. Pharmacological inhibition of JMJD1C similarly attenuated neovascularization in wild-type mice.
Conclusions
JMJD1C acts as a key regulator of pathological ocular angiogenesis through histone demethylation-mediated control of endothelial cholesterol biosynthesis. These findings establish JMJD1C and the Jmjd1c–Srebf2 regulatory axis as promising therapeutic targets for ocular vascular diseases.
{"title":"Endothelial JMJD1C drives pathological ocular neovascularization by activating SREBF2-dependent cholesterol biosynthesis","authors":"Yang Yu , Zhangyu Liu , Jiayu Huang , Xun Qin , Xi Chen , Huiling Nie , Jin Yao , Juxue Li , Qin Jiang","doi":"10.1016/j.freeradbiomed.2026.01.024","DOIUrl":"10.1016/j.freeradbiomed.2026.01.024","url":null,"abstract":"<div><h3>Background</h3><div>Pathological ocular neovascularization is closely linked to aberrant histone modifications, yet the underlying molecular mechanisms remain incompletely defined. This study investigates the role of the histone demethylase JMJD1C and its encoding gene <em>Jmjd1c</em> in driving pathological angiogenesis and evaluates its therapeutic potential in ocular proliferative vascular diseases.</div></div><div><h3>Methods</h3><div><em>Jmjd1c</em> expression was examined in mouse models of ocular neovascularization and in endothelial cells (ECs) using immunostaining, qRT-PCR, and Western blotting. The pro-angiogenic functions of JMJD1C were assessed through EdU incorporation, Transwell migration, tube-formation, and spheroid-sprouting assays in vitro, as well as retinal flat-mount isolectin-B4 staining and H&E staining in vivo. RNA sequencing, immunostaining, qPCR, Western blotting, and ChIP-qPCR were employed to dissect the molecular mechanisms by which JMJD1C regulates pathological angiogenesis.</div></div><div><h3>Results</h3><div>Endothelial-specific deletion of <em>Jmjd1c</em> markedly reduced pathological neovascularization in both oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) models. Loss of JMJD1C impaired endothelial cell proliferation, migration, tube formation, and sprouting angiogenesis. Mechanistically, <em>Jmjd1c</em> deletion suppressed <em>Srebf2</em> transcription and cholesterol biosynthesis by increasing repressive H3K9me2 histone marks in endothelial cells. Pharmacological inhibition of JMJD1C similarly attenuated neovascularization in wild-type mice.</div></div><div><h3>Conclusions</h3><div>JMJD1C acts as a key regulator of pathological ocular angiogenesis through histone demethylation-mediated control of endothelial cholesterol biosynthesis. These findings establish JMJD1C and the <em>Jmjd1c</em>–<em>Srebf2</em> regulatory axis as promising therapeutic targets for ocular vascular diseases.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 181-195"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997725","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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