Antioxidants & redox signaling最新文献

{"title":"Circular RNA-Directed Therapeutic Strategy for Cold-Induced Diabetic Macrovascular Disease.","authors":"Nan Jia, Kangling Xie, Cui Li, Yangjie Li, Yujiao Zong, Jiahao Li, Fan Hu, Ying Cai","doi":"10.1177/15230864251380269","DOIUrl":"https://doi.org/10.1177/15230864251380269","url":null,"abstract":"<p><p><b><i>Aims:</i></b> This study aims to elucidate the molecular mechanisms underlying the alleviation of cold-climate-induced diabetic macrovascular disease (DM-MVD) by targeting hsa_circ_0010154 with gold nanoparticles (AuNPs)-mediated antisense oligonucleotides (ASOs) delivery, combined with aerobic exercise, and to explore the therapeutic effects on glucose and lipid metabolism, inflammation, and oxidative stress. <b><i>Results:</i></b> Significant upregulation of hsa_circ_0010154 in DM-MVD was confirmed through bioinformatics analysis and qRT-PCR validation. The constructed gold nanoparticles-mediated antisense oligonucleotides delivery (AuNPs@ASO) complex exhibited efficient reactive oxygen species-responsive release and effective cellular uptake. Silencing hsa_circ_0010154 led to improved endothelial cell function, reduced inflammation markers, enhanced lipid metabolism, and reduced oxidative stress responses. <i>In vivo</i> studies demonstrated improved cardiac function, vascular remodeling, and enhanced antioxidant enzyme activity. <b><i>Innovation:</i></b> This study introduces a novel approach utilizing AuNPs@ASO targeting hsa_circ_0010154 in conjunction with aerobic exercise to address the complex pathophysiology of cold-climate-induced DM-MVD, presenting a targeted, low-toxicity therapeutic strategy with promising translational potential. <b><i>Conclusion:</i></b> The combined treatment of AuNPs@ASO and aerobic exercise, targeting hsa_circ_0010154, effectively modulates critical pathological pathways involved in DM-MVD, offering a precise and innovative approach for tackling this condition, with implications for clinical translation. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237532","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":"Epstein-Barr Virus Hijacks Redox Signaling via Glutathione Peroxidase 4 to Sustain Latency and Drive Gastric Cancer Progression.","authors":"Duo Shi, Yanhong Zhao, Xia Zhao, Zhiyuan Gong, Wen Liu, Ping Li, Yan Zhang, Bing Luo","doi":"10.1177/15230864251382885","DOIUrl":"https://doi.org/10.1177/15230864251382885","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Epstein-Barr virus (EBV)-associated gastric cancer (GC) accounts for about 9% of GC patients, but its pathogenesis remains unclear. Glutathione peroxidase 4 (GPX4) is an important antioxidant enzyme that is highly expressed in various tumors and is associated with viral infections. This study aimed to clarify the relationship between EBV and GPX4 and the role of GPX4 in the occurrence and development of EBV-associated GC. <b><i>Results:</i></b> EBV infection leads to oxidative stress and excessive generation of reactive oxygen species (ROS) in GC cells. At the same time, EBV upregulates the expression of antioxidant enzyme GPX4 through the latent membrane protein 2A (LMP2A)/p62/Kelch-like ECH-associated protein 1(Keap1)/nuclear factor (erythroid-derived 2)-like 2 (NRF2) axis, eliminating excessive ROS to balance redox homeostasis and maintain its own survival. The high expression of GPX4 in GC inhibits EBV's immediate early lytic gene BZLF1 expression, thereby inhibiting EBV reactivation, and promotes cell migration and proliferation by upregulating lipocalin-2 (LCN2). <b><i>Innovation:</i></b> This study is the first to demonstrate that EBV-induced GPX4 expression <i>via</i> the LMP2A/p62/Keap1/NRF2 axis contributes to both viral latency and tumor progression in GC. <b><i>Conclusion:</i></b> EBV activates the p62/Keap1/NRF2 signaling pathway through LMP2A to upregulate the expression of GPX4, thereby alleviating oxidative stress caused by viral infection and maintaining the redox homeostasis in GC cells. Such enhanced expression not only maintains the latent infection of EBV but also promotes the malignant transformation of GC cells through LCN2. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197781","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":"Endothelial Gasdermin D Induces Mitochondrial Damage and Activates the STING Pathway in Lipopolysaccharide-Accelerated Atherosclerosis.","authors":"Xiaoyue Song, Junqiang Xue, Enyong Su, Shiyao Xie, Xuelin Cheng, Peng Yu, Lili Wei, Ming Liu, Hong Jiang","doi":"10.1177/15230864251380286","DOIUrl":"https://doi.org/10.1177/15230864251380286","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Chronic inflammation is a widely acknowledged contributor to the development of atherosclerosis. Gasdermin D (GSDMD) serves as a key executor of pyroptosis in inflammatory diseases. This study aims to determine the role of endothelial GSDMD in lipopolysaccharide (LPS)-accelerated atherosclerosis and elucidate its underlying molecular mechanisms. <b><i>Results:</i></b> GSDMD expression was aberrantly activated in both LPS-accelerated atherosclerotic animal models and oxidized low-density lipoprotein plus LPS-treated endothelial cell models. Compared with the control, endothelial GSDMD deficiency attenuated the atherogenesis progression and vascular endothelial inflammation induced by LPS and protected against the progression of mitochondrial damage, the release of mitochondrial ROS and mitochondrial DNA, and the activation of the stimulator of interferon genes (STING) pathway both <i>in vivo</i> and <i>in vitro</i>. Mechanistically, endothelial GSDMD expression mediates mitochondrial membrane permeabilization and mitochondrial damage-associated molecular patterns release and triggers the STING pathway to aggravate atherosclerotic progression. In addition, the STING pathway activation was proved to partially reverse the effects of endothelial GSDMD deficiency both <i>in vivo</i> and <i>in vitro</i>. Moreover, the signal transducer and activator of transcription 3 was identified as a positive regulator of GSDMD expression. <b><i>Innovation and Conclusion:</i></b> Our findings elucidate the mechanism by which endothelial GSDMD exerts its atherogenic effects by increasing mitochondrial damage and upregulating the STING pathway in LPS-accelerated atherosclerosis. GSDMD promises to be a critical therapeutic target for atherosclerotic cardiovascular diseases. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184607","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 Regulation of Microvascular Physiology and Pathophysiology: Insights into Therapeutic Strategies and Limitations.","authors":"David A Bulger, Zhan Zhang, Ruinan Hu, Esha K Dave, Puja K Mehta, Kathy K Griendling, Alejandra Valdivia","doi":"10.1177/15230864251372607","DOIUrl":"https://doi.org/10.1177/15230864251372607","url":null,"abstract":"<p><p><b><i>Significance:</i></b> Oxidative mechanisms contribute to both vascular function and pathogenesis of many diseases, but their role in the microvasculature remains poorly understood. <b><i>Recent Advances:</i></b> The role of reactive oxygen and reactive nitrogen species (ROS/RNS) in the vasculature has been well-established for years. Our knowledge of microvascular responses to ROS/RNS has relied on extrapolation of studies performed in large vessels or cultured endothelial cells from large vessels. In healthy tissue, ROS/RNS are implicated in microvascular cell survival and death, angiogenesis, vasodilation, and barrier function, and, in disease, they contribute to increased permeability, leukocyte extravasation, and inflammation. Redox-mediated microvascular dysfunction underlies a multitude of conditions, including cardiovascular diseases, autoimmune diseases, infectious diseases, hemoglobinopathies, inflammatory diseases, vasculitides, and metabolic diseases. <b><i>Critical Issues:</i></b> New single-cell RNA sequencing studies reveal that endothelial cells from different vascular beds have unique gene signatures. Moreover, microvessels respond differently than large vessels, yet findings are frequently extrapolated across vascular beds. Technical challenges have limited our ability to reliably link alterations in ROS/RNS levels to microvascular outcomes. Moreover, successful therapeutics targeting redox signaling in general and in the microvasculature in particular are lacking. While numerous associations exist between common diseases and the microvasculature, the precise contribution of redox-mediated microvascular dysfunction to disease pathogenesis has been challenging. <b><i>Future Directions:</i></b> Additional research in organ-specific microvasculature focusing on the redox mechanisms underlying microvascular function and dysfunction is needed, as well as the development of new targeted therapeutics that can be locally delivered. Comparison of redox responses between different diseases may uncover general mechanisms to exploit therapeutically. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184583","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":"Empagliflozin Attenuates Diabetic Cardiomyopathy via Inhibiting Cardiomyocyte Ferroptosis Through the USP7/NRF2 Signaling Pathway.","authors":"Min Cui, Junwei Zhang, Ziwei Wang, Xiandu Jin, Hanmo Zhang, Shengzheng Zhang, Wenjun Jia, Hao Wu, Zhi Qi, Xin Qi","doi":"10.1177/15230864251377765","DOIUrl":"https://doi.org/10.1177/15230864251377765","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Diabetic cardiomyopathy (DbCM) typically manifests as diastolic dysfunction, and treating heart failure with preserved ejection fraction (HFpEF) is challenging. Empagliflozin (Empa), a sodium-glucose cotransporter 2 inhibitor, reduces hospitalization and mortality in patients with HFpEF and the risk of DbCM. However, the underlying molecular mechanisms and the specific targets remain largely unknown. <b><i>Results:</i></b> Glutathione peroxidase 4 (GPX4) is a key enzyme that mitigates ferroptosis. Empa treatment improved cardiac function, upregulated GPX4 expression, and reduced ferroptosis in DbCM mice. The ferroptosis inducer erastin abolished the protective effects of Empa. Through database screening, we found that nuclear factor erythroid 2-related factor 2 (NRF2) plays an important role in ferroptosis in DbCM. NRF2 was expressed at lower levels in DbCM mice, and its expression significantly increased after Empa treatment. In NRF2-knockout mice, Empa failed to improve the cardiac function of DbCM mice, upregulate the expression of GPX4, and reduce ferroptosis. Moreover, Empa increased NRF2 levels by inhibiting ubiquitin-mediated degradation. A database search predicted that the stability of NRF2 may be regulated by ubiquitin-specific protease 7 (USP7). Immunoprecipitation assays demonstrated that USP7 interacted with NRF2 and mediated its deubiquitination, thereby stabilizing NRF2. Administration of the USP7 inhibitor P5091 abolished the effects of Empa, whereas the use of adeno-associated virus serotype 9 (AAV9)-NRF2 reversed the effects of P5091. <b><i>Innovation and Conclusion:</i></b> Empa attenuated cardiomyocyte ferroptosis in DbCM by stabilizing NRF2 through the USP7/NRF2/GPX4 signaling pathway. Targeting the USP7/NRF2/GPX4 pathway may represent a novel therapeutic strategy for attenuating ferroptosis in DbCM, which has clinical significance. <i>Antioxid. Redox Signal.</i> 00, 000-000. 2022-SYDWLL-000213.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147524","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":"CircGNAQ Promotes Intracranial Aneurysm Formation by Facilitating Vascular Smooth Muscle Cell Phenotypic Switching and Apoptosis.","authors":"Han Zhou, Chao Wang, Wentao Wang, Pin Guo, Yifan Xu, Zhenwen Cui, Xiaolu Li, Shifang Li, Yugong Feng, Tao Yu","doi":"10.1177/15230864251380271","DOIUrl":"https://doi.org/10.1177/15230864251380271","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Intracranial aneurysm (IA) is a critical cerebrovascular disorder strongly linked to phenotypic switching and apoptosis of vascular smooth muscle cells (VSMCs). This study aimed to investigate the role of circGNAQ in IA development and elucidate its underlying molecular mechanisms. <b><i>Results:</i></b> Reverse transcription-quantitative polymerase chain reaction and fluorescence in situ hybridization revealed significant upregulation of circGNAQ in IA tissues, predominantly localized within VSMCs. In vitro, circGNAQ knockdown attenuated hydrogen peroxide-induced VSMC phenotypic switching and apoptosis, whereas circGNAQ overexpression aggravated these pathological processes. RNA pull-down and mass spectrometry demonstrated that circGNAQ specifically binds to serine/arginine-rich splicing factor 1 (SRSF1), promoting its ubiquitination and degradation, thereby destabilizing SRSF1. Cotransfection assays confirmed that SRSF1 functions as a downstream mediator of circGNAQ in regulating VSMC phenotypic switching and apoptosis. In vivo, circGNAQ knockdown significantly suppressed IA formation in a murine model by inhibiting VSMC phenotypic switching and apoptosis. <b><i>Innovation and Conclusion:</i></b> This study identifies circGNAQ as a novel regulator of VSMC phenotypic switching and apoptosis through targeting SRSF1. The findings highlight circGNAQ as a potential therapeutic target for preventing and treating IA. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129872","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":"Nimodipine Blocks Histone-Induced Calcium Overload to Protect Neurons after Traumatic Brain Injury.","authors":"Wei Cao, Yunfeng Xu","doi":"10.1177/15230864251376030","DOIUrl":"https://doi.org/10.1177/15230864251376030","url":null,"abstract":"<p><p><b><i>Aims:</i></b> To investigate if nimodipine alleviates traumatic brain injury (TBI)-induced neuronal apoptosis and neurological deficits by inhibiting extracellular histone-mediated Ca²⁺ influx, mitochondrial damage, and Caspase pathway activation. <b><i>Results:</i></b> In vitro, nimodipine significantly reduced histone-induced Ca²⁺ influx in cortical neurons, reversed by Ca²⁺ activator A23187. It restored neuronal proliferation (↑3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, ↑Ki67+ cells), reduced apoptosis (↓Annexin V/propidium iodide), improved mitochondrial function (↑ΔΨm/adenosine triphosphate, ↓reactive oxygen species/malondialdehyde, ↑Glutathione Peroxidase), and modulated apoptosis markers (↓Bax, ↑Bcl-2). These effects were blocked by A23187 or Caspase activator AD-2646, which increased Cleaved Caspase-3/9 and PARP1. Molecular docking confirmed nimodipine-histone binding. Transcriptomics revealed nimodipine reversed histone-induced dysregulation of Ca²⁺ signaling, mitochondrial apoptosis, and oxidative stress pathways, with Caspase-3 as a key protein-protein interaction node. In vivo, nimodipine improved spatial memory (Morris maze), neurological function (↓modified neurological severity score), and motor coordination (↑rotarod) in TBI mice. It reduced brain lesions (2,3,5-triphenyltetrazolium chloride), neuronal loss (hematoxylin and eosin/Nissl), Ca²⁺ accumulation, and proapoptotic protein expression and restored ΔΨm. Histone coadministration attenuated these benefits. <b><i>Innovation:</i></b> First demonstration that nimodipine directly targets extracellular histone-induced Ca²⁺ influx-a key TBI pathology mechanism-preserving mitochondrial integrity and inhibiting the Caspase cascade, extending beyond its known vasodilatory effects. <b><i>Conclusion:</i></b> Nimodipine mitigates post-TBI neuronal apoptosis and dysfunction by blocking extracellular histone-driven Ca²⁺ overload, preventing mitochondrial damage, and suppressing Caspase activation, significantly improving functional recovery. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079551","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":"Cystathionine γ-Lyase Protects Against Choline-Deficient High-Fat Diet-Induced Metabolic Dysfunction-Associated Steatotic Liver Disease Through the Cysteine-Glutathione Axis in Mice.","authors":"Min Ji Kim, You Ri Park, Gibong Jang, Yong Kwon Han, Isao Ishii, Se Young Jang, Kwon Moo Park","doi":"10.1177/15230864251377735","DOIUrl":"10.1177/15230864251377735","url":null,"abstract":"<p><p><b><i>Aim:</i></b> Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of chronic liver disease, yet its pathogenesis remains incompletely understood. Oxidative stress is thought to play a key role in MASLD progression. This study aimed to investigate the role of cystathionine γ-lyase (CSE), an enzyme essential for cysteine and glutathione (GSH) biosynthesis, in MASLD development. <b><i>Results:</i></b> Choline-deficient high-fat diet (CDHFD) feeding led to elevated aspartate aminotransferase, alanine aminotransferase, hepatic triglyceride accumulation, vacuolization, macrophage infiltration, and cell death in both genotypes, with significantly greater changes observed in <i>Cse</i>^-/- mice. CDHFD also reduced hepatic CSE expression in <i>Cse</i>^+/+ mice and decreased cysteine/GSH levels in both genotypes, with more pronounced reductions in <i>Cse</i>^-/- mice. Furthermore, <i>Cse</i> deletion was associated with increased oxidized glutathione/total GSH ratios and elevated levels of 4-hydroxynonenal and malondialdehyde. Expression of glutathione synthetase and γ-glutamyl transpeptidase was increased by CDHFD in <i>Cse</i>^+/+ mice but blunted in <i>Cse</i>^-/- mice. Furthermore, CSE deficiency exacerbated CDHFD-induced hepatic iron accumulation. <b><i>Innovation:</i></b> Our findings suggest that the CSE-cysteine-GSH axis may serve as a potential therapeutic target for MASLD, providing new intervention strategies beyond traditional approaches. This study provides new insights into the molecular mechanisms of MASLD and supports the development of antioxidant-based therapies. <b><i>Conclusions:</i></b> CSE deficiency exacerbates CDHFD-induced impairments of cysteine-GSH antioxidant axis, leading to hepatic oxidative stress and cell death. This indicates that CSE plays a protective role against MASLD development and progression. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074401","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":"High Incidence of Lethal Ventricular Arrhythmia-Sudden Cardiac Death in Early Myocardial Ischemia: Critical Roles of Cross-Regulation Between Stresses and Calcium Imbalance.","authors":"Xiaojuan Zhang, Mengxuan Zhang, Ye Zhang, Wei Zhang, Huishan Liang, Junyao Lv, Xudong Xiao, Guanghui Zhu, Xiaojun Yu, Minchao Lai, Dian Wang","doi":"10.1177/15230864251372589","DOIUrl":"https://doi.org/10.1177/15230864251372589","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Early myocardial ischemia (MI) predisposes to lethal ventricular arrhythmias (LVA) and subsequent sudden cardiac death (SCD). This study aims to elucidate the roles of cross-regulation between oxidative stress, endoplasmic reticulum (ER) stress, and calcium (Ca²⁺) disturbances in the increased risk of LVA-SCD in early MI. <b><i>Results:</i></b> Both clinical and animal model data showed a higher incidence of SCD within 30 min of MI. In MI animals, T-wave alternans and conduction slowing were observed prior to LVA onset. Optical mapping revealed spatiotemporal electrophysiological discordances, including conduction slowing and alternans in both action potentials and Ca²⁺ transients before LVA, peaking 5-15 min after ischemia onset, with the ischemic zone most affected. Reentrant cycles were observed in isolated MI hearts that developed LVA. SCD animals exhibited elevated mitochondrial and cytosolic reactive oxygen species and Ca²⁺, mitochondrial damage, ER stressors upregulation, and activation of the Ca²⁺/calmodulin-dependent protein kinases (oxidized)-RyR2, ryanodine receptor 2 (CaMKII-RyR2) pathway. These results were partly validated in hypoxic and undernourished myocytes. Targeted interventions, such as MitoTEMPO to mitigate oxidative stress, 4-phenyl butyric acid to inhibit ER stress, and dantrolene or RyR2-S2814A to suppress Ca²⁺ leakage, attenuated disturbances and reduced SCD incidence. <b><i>Innovation and Conclusion:</i></b> We identify a critical 30-min window post-MI, during which redox/ER stress and Ca² imbalance synergistically drive LVA and SCD <i>via</i> the CaMKII-RyR2 pathway. Targeting this pathway could offer a promising strategy to prevent LVA and SCD in early MI. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063353","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":"SIRT3-FOXO3a Isoforms Forge Nuclear-Mitochondrial Links to Combat Sepsis-Induced Cardiomyopathy Oxidative Stress in Mice.","authors":"Xun Luo, Zhengguang Geng, Han Zhang, Wenbo Chen, Junwen Zhang, Siyi Ming, Shiyuan Wang, Mingchun Wang, Haiyun Lei, Bao Fu, Xiaoyun Fu","doi":"10.1177/15230864251374227","DOIUrl":"https://doi.org/10.1177/15230864251374227","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Sepsis-induced cardiomyopathy (SIC) is a serious complication of sepsis. The relationship between SIC and protein acetylation, particularly the balance between acetylation and deacetylation in cardiomyocyte subcellular structures, as well as how nuclear-mitochondrial coordination maintains standard antioxidant stress capacity, remains unclear. This study focused on exploring the nuclear-mitochondrial regulatory mechanisms formed by the interplay of Sirtuin 3 (SIRT3) and Forkhead box O3a (FOXO3a). <b><i>Results:</i></b> <i>In vivo</i>, SIC markers increased significantly in wild-type CLP (Cecal Ligation and Puncture) mice at 72 h (CLP72h) but were partially reversed in CLP72h+oeSIRT3 mice. CLP72h mice exhibited significantly reduced mitochondrial area, aspect ratio, and mtDNA copy number. Echocardiography revealed significantly impaired cardiac function. Western blotting showed significantly decreased nuclear and mitochondrial long-form SIRT3, nuclear long-form and mitochondrial short-form FOXO3a, and mitochondrial superoxide dismutase 2 (SOD2), with significantly increased acetylation in CLP72h mice. <i>In vitro</i>, oeSIRT3 preserved nuclear FOXO3a localization and mitochondrial membrane potential, with CLP72h+oeSIRT3 mice showing significantly reduced oxidative stress. The long form of SIRT3 plays a crucial deacetylation role in SIC and influences SOD2 partially through FOXO3a. <b><i>Innovation:</i></b> This study explored the roles of different SIRT3 and FOXO3a isoforms in combating oxidative stress in SIC through dynamic nucleus-mitochondrial regulation. <b><i>Conclusion:</i></b> This study underscores the critical role of the SIRT3-FOXO3a axis in enhancing mitochondrial antioxidant capacity through a nuclear-mitochondrial network during SIC, offering new insights into molecular mechanisms and potential therapeutic strategies for SIC. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032612","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}