Antioxidants & redox signaling最新文献

{"title":"Physalin A Restores Redox and Mitochondrial Homeostasis to Protect against Diabetic Retinopathy.","authors":"Yan-Ru Xiao, Yow-Wen Hsieh, Wei-Yong Lin, Yu-Sheng Hsieh, Wei-Cheng Jiang, Pei-Ying Pai, Yueh-Hsiung Kuo, Dah-Yuu Lu, Yu-Jung Lin, Wen-Tsong Hsieh","doi":"10.1177/15230864261442217","DOIUrl":"https://doi.org/10.1177/15230864261442217","url":null,"abstract":"<p><strong>Aims: </strong>To determine whether physalin A (PA) safeguards the outer blood-retinal barrier under diabetic stress by engaging nuclear factor erythroid 2-related factor 2 (Nrf2) to restore redox balance and restrain ferroptosis in human retinal pigment epithelial (hRPE) cells and C57BLKS/J Iar -+Lepr^db/+Lepr^db mice.</p><p><strong>Results: </strong>In high-glucose challenged hRPE cells, PA dose-dependently preserved viability, maintained claudin-1/occludin/zonula occludens-1 abundance and membrane localization, and reversed ferroptosis hallmarks (restored solute carrier family 7 member 11 [SLC7A11], SLC3A2, and glutathione peroxidase 4; reduced ferrous iron [Fe²⁺] overload and lipid peroxidation). PA restored glutathione levels, reduced malondialdehyde (MDA), and enhanced the antioxidant defense pathway mediated by Nrf2, including upregulation of heme oxygenase 1, NAD(P)H quinone dehydrogenase 1, and superoxide dismutase 2. Silencing Nrf2 abolished the effects of PA on barrier integrity and ferroptosis suppression, with rebounds in reactive oxygen species, MDA, Fe²⁺, and tight junction loss. In db/db mice treated systemically for 20 weeks, PA reduced Evans Blue leakage, increased retinal thickness, restored RPE tight junction proteins, and normalized mitochondrial architecture by transmission electron microscopy. PA rebalanced mitochondrial dynamics (dynamin 1-like, optic atrophy 1, fission 1, mitofusin 1, FUN14 domain containing 1), increased retinal mitochondrial DNA copy number, and partially stabilized glycemia and weight.</p><p><strong>Conclusion: </strong>PA restores redox tone, restrains ferroptosis, and preserves junctional integrity to protect the diabetic retina, with Nrf2 being indispensable for these benefits. These findings position PA as a promising adjunctive candidate for early diabetic retinopathy and support Nrf2-centered strategies to reinforce the outer blood-retinal barrier. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"15230864261442217"},"PeriodicalIF":6.1,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855772","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":"ROCK Inhibition Reprograms Microglial Polarization to Promote Neuroprotection <i>via</i> NOX2/ROS/TXNIP Suppression.","authors":"Ziyu Wang, Xin Xu, Leshu Wang, Baoyun Guo, Falan Hu, Ziyan Li, Jinhua Chen, Jiyue Wen","doi":"10.1177/15230864261449244","DOIUrl":"https://doi.org/10.1177/15230864261449244","url":null,"abstract":"<p><strong>Aim: </strong>Cerebral ischemia/reperfusion (I/R) injury represents a significant challenge to recanalization therapy for ischemic stroke and is critically influenced by microglial polarization. Although inhibition of Rho-associated protein kinase (ROCK) has been shown to mitigate cerebral I/R injury and associated neuroinflammation, its specific effect on the balance between M1 and M2 (anti-inflammatory) microglial polarization remains incompletely understood. This study aimed to elucidate the role and underlying mechanism of ROCK inhibition in regulating M1 and M2 microglial polarization, using the classical antidepressant fluoxetine as a positive control.</p><p><strong>Results: </strong>ROCK inhibitor fasudil and positive control fluoxetine effectively alleviated cerebral I/R injury and facilitated a shift in microglial polarization from the M1 to the M2 phenotype, both <i>in vivo</i> and <i>in vitro</i>. In the hippocampal tissues of cerebral I/R mice exposed to lipopolysaccharide, we observed an upregulation of thioredoxin-interacting protein (TXNIP) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2). ROCK2 knockdown promoted the M2 microglial polarization, suppressed the expression of NOX2 and TXNIP, and inhibited the activation of NF-κB P65 in mouse hippocampal tissue. Notably, pharmacological inhibition of NF-κB reduced the expression of NOX2 and TXNIP, as well as the production of reactive oxygen species (ROS), in microglia subjected to oxygen-glucose deprivation/reoxygenation. Correspondingly, inhibition of NOX2 also decreased TXNIP expression.Conclusion and Innovation:ROCK inhibition promotes a shift in microglial polarization from the M1 to the M2 subtype by suppressing the NF-κB/NOX2/ROS/TXNIP signaling pathway. This study provides the first evidence demonstrating the mechanism by which ROCK inhibition drives microglial polarization toward the M2 phenotype. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"15230864261449244"},"PeriodicalIF":6.1,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832759","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":"Nitrated Nuclear Receptor Coactivator 4 Contributes to Ferritinophagy in Hyperhomocysteinemia-Induced Liver Injury.","authors":"Wenjing Yan, Xiangning Kong, Jiayin Chai, Xinyu Zhu, Shuai Chen, Yuqing Ding, Yan Li, Chenghua Luo, Wen Wang","doi":"10.1177/15230864261449245","DOIUrl":"https://doi.org/10.1177/15230864261449245","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Aims: &lt;/strong&gt;Hyperhomocysteinemia (HHcy) has been established as a significant risk factor for liver diseases, and its impact on nitrative stress and protein nitration has also been recognized. Nuclear receptor coactivator 4 (NCOA4) is crucial in maintaining iron homeostasis and regulating ferroptosis. However, limited studies are available regarding the post-translational modifications (PTMs) of NCOA4 in liver injury.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Mice fed with a diet containing 2.5% methionine and water with 1.8 g/L DL-Hcy were used in this study. The HHcy-induced liver injury phenotype was assessed through serum aspartate aminotransferase/alanine aminotransferase (AST/ALT), hematoxylin and eosin staining, Masson staining, and real-time quantitative PCR. To further analyze the mechanisms, we conducted tandem mass tag proteomics analysis, Perls blue staining, transmission electron microscopy observation, liver iron content determination, malondialdehyde level, autophagic flux analysis, and detection of indicators related to ferritinophagy-ferroptosis pathway. Additionally, the nitrated NCOA4 was enhanced in HHcy stimulation, especially at sites such as Tyr78, Tyr214, Tyr269, Tyr335, and Tyr608. Peroxynitrite decomposition catalyst (PDC) was used to clear peroxynitrite, while nitrated NCOA4 was inhibited, thereby alleviating liver injury caused by HHcy. We established an HHcy mouse model and confirmed liver injury by elevated serum AST/ALT, histopathology, and fibrosis markers. Mechanistically, HHcy led to hepatic iron overload, lipid peroxidation, and ferroptosis. These effects were associated with upregulated autophagy and NCOA4-mediated ferritinophagy. Importantly, we confirmed &lt;i&gt;in vitro&lt;/i&gt; that HHcy enhanced the nitration of NCOA4 at specific tyrosine residues (Tyr78, 214, 269, 335, 608). Scavenging peroxynitrite with a decomposition catalyst inhibited NCOA4 nitration, subsequently suppressing ferritinophagy, reducing iron overload and lipid peroxidation, and ultimately alleviating liver injury.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Innovation and conclusion: &lt;/strong&gt;We find that HHcy induces nitrative modification at Tyr78/214/269/335/608 sites of NCOA4, upregulating ferritinophagy levels, increasing the intracellular labile iron pool, and triggering iron-dependent lipid peroxidation-driven ferroptosis, thereby promoting the occurrence and development of liver injury. These data indicate that inhibiting nitrated NCOA4, thereby curtailing ferritinophagy, represents a potential therapeutic target for the treatment of HHcy-induced liver injury. This study is the first to identify NCOA4 nitration as a critical PTM that amplifies ferritinophagy under conditions of nitrative stress. We pinpoint five specific nitration sites on NCOA4 and establish a novel causal link between HHcy, protein nitration, and ferroptosis-driven liver injury. Inhibiting the nitrated NCOA4 or upstream peroxynitrite formation to restrain pathological ferritinophagy represents a ","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"15230864261449245"},"PeriodicalIF":6.1,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832780","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":"Preconception Hydroxychloroquine Therapy Restores Placental Function and Improves Pregnancy Outcomes in Obstetric Antiphospholipid Syndrome.","authors":"Yanjun Cai, Mingjie Song, Qingfeng Lv, Hongli Liu, Yuan Wang, Weiyi Qi, Die Jing, Yu Xia, Xietong Wang","doi":"10.1177/15230864261424203","DOIUrl":"10.1177/15230864261424203","url":null,"abstract":"<p><strong>Aims: </strong>Obstetric antiphospholipid syndrome (OAPS), a representative autoimmune disorder driven by antiphospholipid antibodies (aPLs), afflicts 30% of patients with refractory to conventional antithrombotic treatment. Hydroxychloroquine (HCQ) offers adjunctive potential, yet its mechanistic action and critical treatment timing remain undefined. This study establishes the preventive efficacy of preconception HCQ initiation (HCQ-pre) and deciphers its fundamental rescue pathways in OAPS.</p><p><strong>Results: </strong>Clinical data suggested a potential advantage of HCQ-pre compared to post-conception administration (HCQ-post) in optimizing pregnancy outcomes for patients with OAPS. Modeling the pathology of OAPS using human trophoblast organoids revealed that HCQ-pre effectively reverses aPLs-mediated trophoblast dysfunction: increasing cytotrophoblast proliferation (Ki67⁺/TP63⁺) by 20% and restoring their differentiation into extravillous trophoblast (HLA-G⁺) to 93% of control levels, while HCQ-post shows markedly limited efficacy. Mechanistically, HCQ-pre preemptively corrected aPLs-induced redox imbalance by rescuing hypoxia-inducible factor 1-alpha-mediated hypoxia and replenishing antioxidant mediators (NRF2/SOD2/GPX4) <i>via</i> Hippo/YAP and Wnt/β-catenin signaling. Murine OAPS models established that HCQ-pre restores placental perfusion (90% of control levels) by enhancing spiral artery remodeling-with diminished efficacy observed at post-conception administration-thereby attenuating hypoperfusion-induced hypoxic damage and improving pregnancy outcomes.</p><p><strong>Innovation and conclusions: </strong>We redefine HCQ as a proactive placental resetter that neutralizes oxidative stress barriers preconception, thereby liberating trophoblast differentiation capacity. This work positions HCQ-pre as the critical intervention phase-a paradigm shift from reactive adjunct to preemptive root-cause interception, providing the mechanistic foundation for optimizing OAPS management through timely individualized prophylaxis. <i>Antioxid. Redox Signal.</i> 44, 748-769.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"748-769"},"PeriodicalIF":6.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218324","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":"Thioredoxin-1 Inhibits Golgi Stress Induced by Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine.","authors":"Jiaoyang Duan, Xiaowei Sun, Yonghang Wei, Yue Pan, Liping Bai, Fang Yan, Jie Bai","doi":"10.1177/15230864261421607","DOIUrl":"10.1177/15230864261421607","url":null,"abstract":"<p><strong>Aims: </strong>Parkinson's disease (PD) is a common neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the aggregation of alpha-synuclein (α-syn) in Lewy bodies. Emerging studies find that disruption of the Golgi structure and Golgi stress are involved in PD. Thioredoxin-1 (Trx-1) is a redox regulatory protein that protects DA neurons from methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damage. However, whether Trx-1 can protect DA neurons against MPTP-induced Golgi stress is still unknown.</p><p><strong>Results: </strong>We first made sure that MPTP led to the loss of DA neurons in the SNpc and motor impairment in mice, which was reversed in Trx-1 overexpression mice. Trx-1 overexpression suppressed Golgi apparatus fragmentation, α-syn aggregation, oxidative stress, and protein kinase C zeta expression increased by MPTP. Trx-1 overexpression restored the colocalization of Trx-1 and tyrosine hydroxylase with Golgi matrix protein 130 (GM130), decreased by MPTP. Moreover, Trx-1 overexpression suppressed the increased co-localization of Leucine-rich repeat kinase 2 and Ras-associated binding protein 29 with vacuolar protein sorting-associated protein 52 induced by MPTP. Trx-1 overexpression suppressed the expression changes of ADP-ribosylation factor 4 and heat shock protein 47, and their colocalization with GM130 induced by MPTP.</p><p><strong>Innovation: </strong>Our study reveals a novel mechanism, whereby Trx-1 inhibits Golgi stress in DA neuron induced by MPTP.</p><p><strong>Conclusions: </strong>These results suggest that Trx-1 may regulate the development of PD through inhibiting Golgi stress and is a potential new molecular target and therapeutic strategy for Golgi stress involved in PD. <i>Antioxid. Redox Signal.</i> 44, 661-675.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"661-675"},"PeriodicalIF":6.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146140589","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":"Dysregulated Copper Metabolism-Induced Cuproptosis Contributes to Mitochondrial Dysfunction and Macrophage Inflammatory Response in Acute Lung Injury.","authors":"Shuyang Chen, Zheng Zhou, Yajun Wang, Dong Yang, Jinjun Jiang, Shujing Chen","doi":"10.1177/15230864261425887","DOIUrl":"10.1177/15230864261425887","url":null,"abstract":"<p><strong>Aims: </strong>To determine whether dysregulated copper metabolism and cuproptosis contribute to acute lung injury (ALI), and to evaluate whether targeting copper homeostasis mitigates lung inflammation and injury.</p><p><strong>Results: </strong>Integrative analysis of RNA-seq data from patients with severe community-acquired pneumonia revealed increased enrichment of copper metabolism-related gene sets and differential expression of cuproptosis-related genes. Notably, immune deconvolution of patient RNA-seq data demonstrated prominent macrophage enrichment, suggesting that macrophages represent a major cell group in which dysregulated copper metabolism may occur during ALI. In a lipopolysaccharide (LPS)-induced mouse ALI model, lung copper levels were elevated, accompanied by molecular features of cuproptosis, including increased DLAT oligomerization and destabilization of Fe-S cluster proteins. Pretreatment with the copper chelator tetrathiomolybdate alleviated lung injury and inflammatory response, while suppressing cuproptosis-related molecular features <i>in vivo</i>. In alveolar macrophages, LPS challenge increased intracellular Cu⁺ concentration and promoted DLAT oligomerization, and impaired Fe-S protein stability. Mechanistically, both copper chelation and knockdown of upstream cuproptosis regulator reduced DLAT oligomerization, restored Fe-S proteins, alleviated mitochondrial dysfunction, and decreased CD86⁺ macrophage polarization. Importantly, altered expression of copper transporters was observed, suggesting a remodeling of copper metabolic homeostasis during ALI.</p><p><strong>Innovation and conclusion: </strong>This study identifies cuproptosis as a previously unrecognized driver of ALI, mechanistically linking copper dysregulation to mitochondrial damage and inflammatory activation of alveolar macrophages, and demonstrates the therapeutic benefit of copper chelation or cuproptosis suppression. <i>Antioxid. Redox Signal.</i> 44, 770-791.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"770-791"},"PeriodicalIF":6.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147316133","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":"Metabolic Reprogramming and Ferroptosis: Unlocking New Therapeutic Frontiers in Cancer and Diabetes.","authors":"Yan Huo, Yaoxiong Xia, Qiuyi Zhang, Yanjie Li, Yu Zhao, Zhiyong Li, Danyu Zhu, Fangpei Ma, Zhun Gu, Nannan Zhang, Yanping Gao","doi":"10.1177/15230864261421487","DOIUrl":"10.1177/15230864261421487","url":null,"abstract":"<p><strong>Significance: </strong>Ferroptosis, an iron- and lipid peroxidation-dependent mode of programmed cell death, is presently realized as a converging mediator that bridges redox imbalance and metabolic dysfunction. Differing from apoptosis and necroptosis, ferroptosis involves iron homeostasis, glutathione depletion, and redox lipid damage. Thus, it becomes the intersection of metabolic reprogramming and redox signaling. Ferroptosis is a double-edged metabolic vulnerability and adaptive resistance pathway in malignancy.</p><p><strong>Recent advances: </strong>Oncogenic signaling cascades such as PI3K/Akt/mTOR and AMPK restructure glucose and lipid metabolism to regulate ferroptotic sensitivity, whereas cancer cells destabilize antioxidant defense pathways such as Xc^--GSH-GPX4 and FSP1-CoQ10-NAD(P)H pathways to evade ferroptotic cell death. Pharmacological inducers erastin, RSL3, and sorafenib reverse oxidative imbalance, enhance antitumor effect, and immune modulation in the tumor microenvironment. In diabetic mellitus complications, ferroptosis is responsible for β-cell deterioration, insulin resistance, and vascular injury. Hyperglycemia-induced oxidative stress and dysregulated GPX4 facilitate lipid peroxidation and ferroptotic cell death in pancreatic β-cells, while iron overload and mitochondrial dysfunctions facilitate ferroptotic injury in diabetic cardiomyopathy, nephropathy, retinopathy, and foot ulcer. These observations position ferroptosis as a crucial metabolically reorganized hub of organ damage.</p><p><strong>Critical issues: </strong>Despite rapid advancements, foundational challenges persist, including the identification of ferroptosis-specific biomarkers, tissue-specific thresholds, and mechanisms for neutralizing off-target toxicity.</p><p><strong>Future directions: </strong>Recently developed technologies such as CRISPR-based functional genomics, metabolomics, and AI-powered modeling represent new-age tools in defining ferroptosis networks and precision therapeutics design. Integration of the regulation of normal physiological ferroptosis into cancer and diabetes therapy has the potential to redefine redox-targeted therapy and metabolic medicine. <i>Antioxid. Redox Signal.</i> 44, 676-711.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"676-711"},"PeriodicalIF":6.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177617","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":"Epitranscriptomic Control of Vascular Smooth Muscle Cell Ferroptosis by WTAP in the Pathogenesis of Vascular Restenosis.","authors":"Yanwei Yin, Fangmeng Lei, Zihe Dang, Shaoqing Cao, Zhikun Zhao","doi":"10.1177/15230864261424217","DOIUrl":"10.1177/15230864261424217","url":null,"abstract":"<p><strong>Aims: </strong>Vascular restenosis is a common complication following vascular interventions, driven by abnormal proliferation and phenotypic switching of vascular smooth muscle cells (VSMCs). Ferroptosis, an iron-dependent regulated cell death, has been implicated in VSMC dysfunction and vascular remodeling. However, the epitranscriptomic regulation of ferroptosis in VSMCs remains unclear.This study investigates the role of Wilms tumor suppressor gene WT1-associated protein (WTAP), a key N6-methyladenosine (m6A) RNA methylation regulator, in controlling ferroptosis of VSMCs during vascular restenosis.</p><p><strong>Results: </strong>A balloon injury rat model and platelet-derived growth factor-BB-stimulated VSMCs were used to mimic vascular restenosis. WTAP expression and global m6A levels were assessed. Functional assays evaluated the effects of WTAP overexpression on ferroptosis markers, reactive oxygen species (ROS), lipid peroxidation, and VSMC proliferation. Mechanistic studies explored WTAP-mediated m6A modification of the long non-coding RNA growth arrest specific 5 (GAS5), its interaction with enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), and downstream regulation of interferon regulatory factor 4 (IRF4) and ferritin heavy chain 1 (FTH1).WTAP expression and global m6A levels were significantly reduced in restenotic tissues and cells. WTAP overexpression restored m6A modification on GAS5, enhancing its stability <i>via</i> YTH domain family member 1. GAS5 inhibited EZH2-mediated H3K27me3 repression of IRF4, which transcriptionally activated FTH1, suppressing ferroptosis. WTAP overexpression decreased ROS, lipid peroxidation, and VSMC proliferation, while knockdown of GAS5 or IRF4 partially reversed these effects.</p><p><strong>Innovation: </strong>Our study is the first to identify that the WTAP/GAS5/IRF4 axis suppresses PDGF-BB-induced cell proliferation by inhibiting ferroptosis in VSMCs, and alleviates vascular restenosis caused by balloon injury.</p><p><strong>Conclusion: </strong>WTAP epitranscriptomically regulates VSMC ferroptosis <i>via</i> the GAS5/EZH2/IRF4/FTH1 axis, revealing a novel mechanism in vascular restenosis pathogenesis and a potential therapeutic target. <i>Antioxid. Redox Signal.</i> 44, 726-747.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"726-747"},"PeriodicalIF":6.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147363708","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":"Dietary Antioxidants and Cardiovascular Health: Insights from a 14-Year UK Biobank Trajectory Analysis.","authors":"Ru Fu, Tao Liu, Ye Chen, Miao Huang, Xiaogang Li, Weihong Jiang","doi":"10.1177/15230864261421605","DOIUrl":"10.1177/15230864261421605","url":null,"abstract":"<p><strong>Background: </strong>To evaluate the impact of the composite dietary antioxidant index (CDAI) on the progression from hypertension (HT) to cardiovascular diseases (CVDs) and subsequent death.</p><p><strong>Methods: </strong>This prospective study included 100,193 participants (median age 55) initially free of HT and CVDs from the UK Biobank. The CDAI was calculated from the intake of six dietary antioxidants, including manganese, selenium, zinc, and vitamins A, C, and E. Multivariable Cox regression analysis assessed the relationship between CDAI and the risks of HT, CVDs, and all-cause mortality. Multistate models were used to examine the impact of CDAI levels on CVD progression trajectories.</p><p><strong>Results: </strong>During a median follow-up of 14.10 years, 11,998 participants developed HT, 3656 developed CVDs, and 4169 died. CDAI was inversely associated with the risk of adverse outcomes, including HT, CVDs, and death. Compared with the lowest CDAI quartile, the adjusted hazard ratios (HRs; confidence intervals [CIs]) for the highest quartile in transitions from baseline to HT, to CVDs, and to death were 0.913 (0.868-0.960), 0.890 (0.799-0.992), and 0.850 (0.767-0.942), respectively. An association between the highest quartile CDAI and reduced risk was also observed in transitions from HT to CVDs (HR: 0.698; 95% CI: 0.558-0.872) and from HT to death (HR: 0.803; 95% CI: 0.648-0.995). Mediation analysis indicates that the reduction in CVD and mortality risk associated with CDAI primarily depends on its direct effect rather than its indirect effect through HT.</p><p><strong>Conclusions: </strong>The CDAI influences the progression of CVD trajectories, underscoring the need for dietary adjustments to elevate CDAI levels in CVD health management. <i>Antioxid. Redox Signal.</i> 44, 712-725.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"712-725"},"PeriodicalIF":6.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146140628","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":"Thioredoxin 1 Suppresses TXNIP-Driven Control of Glucose Metabolism in Human Cells.","authors":"Shayida Maimaiti, Markus Dagnell, Lucia Coppo, Wenchao Zhao, Peter Geserick, Kai Kappert, Elias S J Arnér","doi":"10.1177/15230864261421616","DOIUrl":"10.1177/15230864261421616","url":null,"abstract":"<p><strong>Aims: </strong>Cytosolic thioredoxin 1 (Trx1, TXN, TRX) is a central player in redox control. Thioredoxin interacting protein (TXNIP), an α-arrestin regulating glucose metabolism and inflammation, is widely regarded to inhibit TRX activity. However, the interactions between the two proteins across various cellular contexts remain poorly understood; in addition, only a limited number of studies have yet been conducted in human primary cells. We thus aimed here to investigate the functional relationship between TRX and TXNIP in human primary cells. We studied whether TXNIP inhibits TRX cellular activity in these primary cells and how this interaction influences cellular redox biology or glucose metabolism.</p><p><strong>Results: </strong>In primary cells, TXNIP deficiency did not increase cellular TRX activity. Instead, TXNIP deficiency elevated PGC-1α and PDK4 transcripts, increased PDHA1 Ser293 phosphorylation, and raised basal GLUT4, consistent with enhanced glucose uptake and restrained flux through the pyruvate dehydrogenase complex. Conversely, lowering TRX expression levels triggered higher TXNIP levels. This in turn correlated with suppressed transcripts for PGC-1α and PDK4, a lower extent of PDHA1 phosphorylation at Ser293, and decreased glucose uptake.</p><p><strong>Innovation: </strong>Our findings suggest that TXNIP, against common belief, may not necessarily be an endogenous inhibitor of TRX but, rather, that TRX can be an inhibitor of TXNIP.</p><p><strong>Conclusion: </strong>This study reveals that the key intracellular redox protein TRX inversely regulates TXNIP, suggesting that modulation of the TRX system may provide a previously unrecognized therapeutic avenue for modulation of glucose metabolism. <i>Antioxid. Redox Signal.</i> 44, 643-660.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"643-660"},"PeriodicalIF":6.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147281680","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}