Redox Biology最新文献

{"title":"GluA2 palmitoylation by SELENOK modulates AMPAR assembly and synaptic plasticity in Alzheimer's disease","authors":"Jiaying Peng ,&nbsp;Zhiyu Cai ,&nbsp;Pei Ouyang ,&nbsp;Shujing Lin ,&nbsp;Shurui Zhang ,&nbsp;Danchan Liang ,&nbsp;Ziqi Feng ,&nbsp;Changbin Chen ,&nbsp;Xilin Ye ,&nbsp;Guoli Song ,&nbsp;Zhonghao Zhang","doi":"10.1016/j.redox.2025.103831","DOIUrl":"10.1016/j.redox.2025.103831","url":null,"abstract":"<div><div>Se is essential for central nervous system function, and its deficiency is strongly associated with cognitive decline, especially in neurodegenerative disorders such as Alzheimer's disease (AD). Although Se exerts its effects through selenoproteins, the molecular basis of its neuroprotective action remains unclear. Among selenoproteins, the endoplasmic reticulum (ER)-resident selenoprotein K (SELENOK) is closely linked to cognitive function and therapeutic potential in AD. Here, we examined how SELENOK regulates synaptic plasticity and contributes to Se-mediated neuroprotection in AD. Using age-gradient SELENOK knockout models and palmitoyl-proteomics, we identified GluA2 (formerly GluR2) as a key downstream target. Mechanistically, SELENOK enhanced the activity of DHHC6, an ER-localized palmitoyltransferase, to promote GluA2 palmitoylation, facilitating its ER retention and efficient assembly of AMPA-type glutamate receptors (AMPARs). Notably, GluA2 palmitoylation was reduced in both AD model mice and postmortem brains of patients with AD. Importantly, neuronal overexpression of SELENOK in the hippocampus restored synaptic plasticity and cognitive function in AD mice. Overall, this study uncovers a novel SELENOK-dependent mechanism regulating AMPAR assembly, offering experimental support for developing Se-based therapeutic strategies for AD.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103831"},"PeriodicalIF":11.9,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deregulated Nrf2-Keap1-BACH1 axis in autism spectrum disorder","authors":"Andrea Vallese ,&nbsp;Sara Melija ,&nbsp;Joussef Hayek ,&nbsp;Alessandra Pecorelli ,&nbsp;Giuseppe Valacchi","doi":"10.1016/j.redox.2025.103837","DOIUrl":"10.1016/j.redox.2025.103837","url":null,"abstract":"<div><div>Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders characterized by impairments in social communication, restricted interests, and repetitive behaviors. Although its etiology remains incompletely understood, increasing evidence suggests a multifactorial origin involving genetic alterations, immune dysregulation, and environmental exposures. The aim of this study was to investigate the redox-sensitive Nrf2 signaling pathway in primary dermal fibroblasts isolated from ASD patients. Our results revealed constitutive activation of Nrf2, accompanied by reduced expression of its downstream target heme oxygenase-1 (HO1) and marked nuclear accumulation of the transcriptional repressor BACH1 in ASD cells. Moreover, ASD fibroblasts failed to increase Nrf2 nuclear translocation upon sulforaphane (SFN) stimulation, a response consistent with elevated basal levels of Keap1, a negative regulator that sequesters Nrf2 in the cytoplasm. Notably, treatment with hemin, known to induce nuclear export and degradation of BACH1, successfully restored HO1 gene and protein expression and ameliorated impaired mitochondrial function in ASD fibroblasts, as suggested by the decrease of mtROS levels and the restored mitochondrial membrane potential. Collectively, these results identify a dysregulation of the Nrf2-Keap1-BACH1 axis in ASD and suggest that pharmacological targeting of this pathway may offer therapeutic potential to correct the redox imbalance associated with the disorder.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103837"},"PeriodicalIF":11.9,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144893132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive transcriptome sequencing and biochemical studies revealed that acrolein induced lung injury in BEAS-2B cells and male rats through the lncRNA MIR155HG/miR-155-5p/CD200R1 and Nrf2/SLC7A11/GPX4 ferroptosis pathways","authors":"Dan Liu ,&nbsp;Hui Yu ,&nbsp;Zhicun Liu ,&nbsp;Le Wang ,&nbsp;Dawo Liu ,&nbsp;Xiangyu Cao","doi":"10.1016/j.redox.2025.103832","DOIUrl":"10.1016/j.redox.2025.103832","url":null,"abstract":"<div><div>Acrolein is a significant high priority hazardous air pollutant. This research explore the relationship of acrolein-induced ferroptosis with the pathogenesis of lung injury by combining cellular, transcriptome, and animal-level studies. The results <em>in vivo</em> and <em>in vitro</em> models indicated that a total of 18,868 differenced lncRNAs and 15,639 differenced mRNAs were obtained after acrolein exposure. After screening, 636 lncRNAs and 214 mRNAs were obviously different of the acrolein injured group with the control group. Differential genes were mainly enriched in the iron ion binding, tissue homeostasis, etc. Among them, lncRNA MIR155HG significantly responded to the toxic effects of acrolein, the knockdown of lncRNA MIR155HG could inhibit miR-155-5p expression, promote CD200R1 expression, and improve cell viability. Furthermore, it effectively inhibited acrolein-induced the activation of ferroptosis pathway in BEAS-2B cells and lung tissue, indicating that lncRNA MIR155HG might be a potential new target for the inhibition of acrolein toxicity. LncRNA-MIR155HG/miR-155-5p/CD200R1 axis played an significant role in the lung injury, and induced ferroptosis by regulating the Nrf2/SLC7A11/GPX4 pathway. This study is the first to reveal that acrolein exposure significantly affected lncRNA and mRNA expression in BEAS-2B cells, and found that lncRNA MIR155HG effectively regulated acrolein-induced ferroptosis pathway, providing novel insights for the treatment of lung injury.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103832"},"PeriodicalIF":11.9,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144893131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inducible skeletal muscle-specific p53 deletion alleviates high-fat diet-induced insulin resistance by modulating mitochondria-associated membrane in obese mice","authors":"Soyoung Park ,&nbsp;Jin Ki Jung ,&nbsp;Jung-Yoon Heo ,&nbsp;Themis Thoudam ,&nbsp;Su-Yeon Jeong ,&nbsp;Seok-Hui Kang ,&nbsp;Chang-Hoon Woo ,&nbsp;Hyoung Chul Choi ,&nbsp;In-kyu Lee ,&nbsp;Jinmyoung Dan ,&nbsp;Jongsoon Lee ,&nbsp;Jae-Ryong Kim ,&nbsp;So-Young Park","doi":"10.1016/j.redox.2025.103828","DOIUrl":"10.1016/j.redox.2025.103828","url":null,"abstract":"<div><div>p53 has been implicated in metabolic regulation, but its role in obesity-induced skeletal muscle insulin resistance remains incompletely understood. This study aimed to determine the functional contribution of skeletal muscle p53 to insulin resistance and mitochondrial dysfunction, particularly in the context of obesity. We demonstrate that inducible, skeletal muscle-specific deletion of p53 (iMp53 KO) significantly improves insulin sensitivity in high-fat diet (HFD)-induced obese mice, with no effect in chow-fed controls. This metabolic improvement was accompanied by enhanced mitochondrial respiration and membrane potential, as well as reduced mitochondrial calcium overload in palmitate-treated C2C12 myotubes. Electron microscopy and immunoblotting revealed a marked reduction in mitochondria-associated membrane (MAM) area and decreased levels of MAM components (IP3R, VDAC, GRP75) in iMp53 KO muscle. Co-immunoprecipitation assays demonstrated physical interactions between p53 and MAM proteins, supporting a role for p53 in promoting MAM formation under obese conditions. Consistently, skeletal muscle from patients with type 2 diabetes exhibited elevated expression of both p53 and MAM markers, with a positive correlation between them. These findings suggest that p53 plays an important role in modulating ER–mitochondrial contacts and mitochondrial homeostasis in skeletal muscle and suggest its contribution to obesity-induced insulin resistance. This study provides new mechanistic insight into the pathological role of p53 in muscle metabolism.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103828"},"PeriodicalIF":11.9,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144894871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N-butylphthalide (NBP) and ligustrazine (TMP) triazole hybrids target the KEAP1-NRF2 pathway to inhibit ferroptosis and exert brain neuroprotectivity","authors":"Guangyu Li ,&nbsp;Haiyan Xiao ,&nbsp;Chenwei Zuo,&nbsp;Haochen Xie,&nbsp;Xiaolin Wang,&nbsp;Jiaxin Wang,&nbsp;Ying Liu,&nbsp;Quanxing Hou,&nbsp;Guibo Sun,&nbsp;Yu Tian","doi":"10.1016/j.redox.2025.103835","DOIUrl":"10.1016/j.redox.2025.103835","url":null,"abstract":"<div><div>Ischemic stroke is a life-threatening disease, its pathological progression involves multiple factors, including oxidative stress, apoptosis, and ferroptosis. Our previous study demonstrated that hybridizing <em>N</em>-butylphthalide (NBP) with ligustrazine (TMP) yielded promising anti-ischemic compounds. In this study, we further introduced a triazole structure into NBP-TMP hybrids and synthesized 20 novel compounds. Their neuroprotective activities were evaluated on OGD/R induced SH-SY5Y cells and primary hippocampal neurons, leading to the identification of preferred compounds <strong>8a</strong>, <strong>8b</strong> and <strong>8d</strong> at the concentration of 6.25 μM, which surpassed the neuroprotective activity of the positive control NBP. Among them, 8a exhibited the highest protective activity, with a protection percentage of 75.6 %. Further mechanistic studies revealed that compounds <strong>8a</strong>, <strong>8b</strong> and <strong>8d</strong> maintained intracellular redox homeostasis to resist oxidative stress and inhibit apoptosis <em>in vitro</em>. Specifically, compound <strong>8a</strong> exerted neuroprotective effects by modulating the KEAP1-NRF2 pathway: it bound to KEAP1, enhanced NRF2 dissociation and nuclear translocation, facilitated the generation of downstream antioxidant factors, thereby reducing intracellular ‌reactive oxygen species (ROS) levels and effectively protecting neuronal mitochondria. Finally, <em>in vivo</em> experiments demonstrated that compound <strong>8a</strong> (20 mg/kg) significantly ameliorated cerebral injury in rats with ischemia-reperfusion injury. Furthermore, it reduced cerebral oxidative stress by modulating the KEAP1-NRF2 pathway and inhibited neuronal apoptosis and ferroptosis in the brain, which is consistent with the results <em>in vitro</em>. In conclusion, our results indicated that 8a serves as a promising candidate for stroke treatment and may facilitate the development of future anti-ischemic drugs.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103835"},"PeriodicalIF":11.9,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144892155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"p53 promote oxidative stress, neuroinflammation and behavioral disorders via DDIT4-NF-κB signaling pathway","authors":"Kaiqi Zhang ,&nbsp;Yongsi Zhao ,&nbsp;Xiao Chen ,&nbsp;Ye Li ,&nbsp;Tian Lan ,&nbsp;Mengni Chang ,&nbsp;Wenjing Wang ,&nbsp;Changmin Wang ,&nbsp;Xianghua Zhuang ,&nbsp;Bin Zhang ,&nbsp;Shuyan Yu","doi":"10.1016/j.redox.2025.103836","DOIUrl":"10.1016/j.redox.2025.103836","url":null,"abstract":"<div><div>Depression is a mood disorder characterized by persistent emotional and behavioral dysregulation. Oxidative stress-induced neuronal damage is increasingly recognized as a critical risk factor contributing to the pathogenesis of depression. However, the potential molecular mechanisms and therapeutic targets underlying brain homeostasis disruption induced by neuroinflammatory responses remain unclear. The polyphenolic compound curcumin has been shown to exert neuroprotective effects and partially alleviate depression-related behavioral symptoms through its anti-oxidative properties. However, the molecular mechanisms and therapeutic targets underlying curcumin's ability to ameliorate oxidative stress-induced behavioral abnormalities in specific brain regions remain insufficiently defined. In this study, we demonstrate that chronic administration of corticosterone (CORT) induces pronounced depression- and anxiety-like behaviors in mice, accompanied by marked oxidative stress, neuroinflammation, and disrupted synaptic plasticity within the medial prefrontal cortex (mPFC). Curcumin treatment significantly ameliorated these behavioral and neuropathological abnormalities by enhancing antioxidant capacity, suppressing inflammatory cytokine production and restoring dendritic architecture. Transcriptomic profiling and network pharmacology identified the p53-DDIT4-NF-κB signaling as a key signaling hub underlying these effects. Pharmacological inhibition of p53 with pifithrin-α (PFT-α) mimicked the antidepressant-like effects of curcumin, whereas activation with NSC697923 abolished them. These findings support curcumin may serve as a promising strategy for anti-oxidative stress and <em>anti</em>-neuroinflammation in depression via targeting p53-DDIT4-NF-κB signaling.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103836"},"PeriodicalIF":11.9,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative stress-induced ZEB1 acetylation drives a hybrid epithelial-mesenchymal phenotype and promotes lung metastasis in triple-negative breast cancer","authors":"Min Guo ,&nbsp;Yan-Jing Wang ,&nbsp;Jie Shi ,&nbsp;Li-Xia Cao ,&nbsp;Yang Ou ,&nbsp;Xiao Jia ,&nbsp;Chun-Chun Qi ,&nbsp;Zhao-Xian Li ,&nbsp;Yu-Xin Liu ,&nbsp;Si-Yu Zuo ,&nbsp;Qiu-Ying Shuai ,&nbsp;Tian-Wen Yu ,&nbsp;Hua-Yu Hu ,&nbsp;Xiao Chen ,&nbsp;Meng-Dan Feng ,&nbsp;Yao Xue ,&nbsp;Hang Wang ,&nbsp;Pei-Qing Sun ,&nbsp;Lei Liu ,&nbsp;Yi Shi ,&nbsp;Shuang Yang","doi":"10.1016/j.redox.2025.103834","DOIUrl":"10.1016/j.redox.2025.103834","url":null,"abstract":"<div><div>While epithelial-mesenchymal plasticity (EMP) drives cancer metastasis, its regulation by redox dynamics remains poorly understood. Herein, we identified an oxidative stress-responsive CBP/SIRT1 axis that coordinated ZEB1 acetylation at K1108 to promote lung metastasis in triple-negative breast cancer (TNBC). Mechanistically, the biochemical and functional analyses revealed that the dual-acetyltransferase CBP, through stabilization and autoacetylation by oxidative stress, formed a dynamic partnership with SIRT1 to execute precision lysine modification. This post-translational rheostat triggered the functional metamorphosis of ZEB1. During this process, ZEB1 dissociation from the transcriptional corepressor CtBP, while recruiting CBP, converts ZEB1 into a transcriptional activator of epithelial genes. The resulting hybrid epithelial‒mesenchymal phenotype orchestrated dual metastatic competence-maintaining stromal interaction capacity through partial epithelial‒mesenchymal transition (EMT) while establishing NADPH-driven redox supremacy to circumvent ferroptosis. Importantly, this acetyl switch of ZEB1 revealed a metastasis-specific therapeutic vulnerability in TNBC. Our work thus highlighted ZEB1 acetylation as a redox-interpreted mechanism coupling phenotypic plasticity with stress resistance, proposing targeted disruption of this protein post-translational modification (PTM) circuit as a precision strategy against metastatic progression.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103834"},"PeriodicalIF":11.9,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144892154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SALSA: a novel flow cytometry assay to detect ascorbate at the single-cell level","authors":"Bella Lee ,&nbsp;Wendy Wan-Ting Chou ,&nbsp;Heng-Yi Chen ,&nbsp;Dena Mossad ,&nbsp;Michael Hsu ,&nbsp;Bridget Bowman ,&nbsp;Kartick Patra ,&nbsp;Huan Zhang ,&nbsp;Fang-Yun Lay ,&nbsp;Frederick A. Villamena ,&nbsp;Gang Xin ,&nbsp;Richard S Bruno ,&nbsp;Mark Levine ,&nbsp;Jiangjiang Zhu ,&nbsp;Fernanda Novais ,&nbsp;Chan-Wang Jerry Lio","doi":"10.1016/j.redox.2025.103823","DOIUrl":"10.1016/j.redox.2025.103823","url":null,"abstract":"<div><div>Ascorbate (AA) is an essential antioxidant and enzymatic cofactor with emerging roles in epigenetic regulation, redox biology, and immune function. However, single-cell quantification of intracellular AA has remained technically challenging. Here, we present SALSA (Single-cell Ascorbate Level Sensing Assay), a novel flow cytometry-based method that enables sensitive, specific detection of intracellular AA at the single-cell level. Inspired by the mechanism of the <em>in vitro</em> AA assay, we identified 4,5-diaminofluorescein (DAF-2), a common nitric oxide (NO) probe, as a selective AA reporter. We showed that the chemical oxidation of AA into dehydroascorbic acid (DHA) facilitated its reaction with DAF-2 to form a highly fluorescent product. Surprisingly, the DAF-2-DHA adduct exhibits a red-shifted emission spectrum distinguishable from those of DAF-2 alone or its NO-reactive product. This spectral shift enables the differentiation of signals into two channels, SALSA^Verde (green) and SALSA^Roja (red-orange), with SALSA^Roja offering superior sensitivity and minimal NO interference. SALSA is quantitative, with a strong linear correlation between signal intensity and intracellular AA concentration. Using SALSA and CRISPR, we identified SVCT2 as the major AA transporter in a human cell line model. Applying SALSA to immune profiling revealed previously unappreciated heterogeneity in AA levels across immune subsets and developmental stages. Together, these findings establish SALSA as a robust and accessible method for probing AA dynamics at single-cell resolution, with broad potential applications in redox biology, immunology, and metabolism.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103823"},"PeriodicalIF":11.9,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144892156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective inhibition of NOX2 after status epilepticus attenuates epileptogenesis and cognitive impairment: A sex-dependent study","authors":"Prince Kumar Singh ,&nbsp;Shweta Maurya ,&nbsp;Aseel Saadi ,&nbsp;Taige Zhang ,&nbsp;Andreas Lieb ,&nbsp;Tawfeeq Shekh-Ahmad","doi":"10.1016/j.redox.2025.103830","DOIUrl":"10.1016/j.redox.2025.103830","url":null,"abstract":"<div><div>Epilepsy, a chronic neurological disorder affecting approximately 1 % of the global population, is characterized by recurrent seizures that are often refractory to current antiseizure medications (ASMs). These pharmacotherapies predominantly suppress symptoms without intervening in the underlying pathophysiological cascade, which includes persistent oxidative stress and neuroinflammation, key drivers of epileptogenesis and pharmacoresistance. Among the primary enzymatic sources of reactive oxygen species (ROS), NADPH oxidase 2 (NOX2) has emerged as a central mediator of redox imbalance and neuroimmune activation in the brain. However, the sex-specific roles of NOX2 and its modulation as a therapeutic strategy remain largely unexplored.</div><div>Here, we investigated the therapeutic efficacy of GSK2795039, a selective and functionally active NOX2 inhibitor, in a kainic acid (KA)-induced status epilepticus (SE) rat model. We examined both acute and chronic outcomes of early NOX2 inhibition on oxidative stress, neuroinflammation, hippocampal neurodegeneration, and cognitive function, incorporating rigorous analysis of sex-dependent responses. Long-term effects on epileptogenesis were assessed using continuous 24/7 video-electrocorticographic (vECoG) monitoring.</div><div>Our results revealed that early GSK2795039 intervention significantly attenuated SE-induced oxidative damage, pro-inflammatory cytokine expression, and neuronal death, thereby mitigating the development of spontaneous recurrent seizures. Notably, male rats exhibited a more robust therapeutic response, including a marked reduction in seizure burden and improved cognitive performance, whereas females displayed a more modest response, suggesting the presence of compensatory or NOX2-independent antioxidant mechanisms.</div><div>These findings underscore the pivotal role of NOX2-derived ROS in driving epileptogenesis and highlight the translational potential of NOX2-targeted therapies. Importantly, our study revealed a clear sex divergence in therapeutic outcomes, reinforcing the necessity of integrating sex as a critical biological variable in preclinical and clinical strategies aimed at disease modification in epilepsy.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103830"},"PeriodicalIF":11.9,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144903013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophages and macrophage extracellular vesicles confer cancer ferroptosis resistance via PRDX6-mediated mitophagy inhibition","authors":"Naisheng Zheng,&nbsp;Fuli Li,&nbsp;Qing Huang,&nbsp;Xian Huang,&nbsp;Tomasz Maj","doi":"10.1016/j.redox.2025.103826","DOIUrl":"10.1016/j.redox.2025.103826","url":null,"abstract":"<div><div>Ferroptosis has emerged as a promising therapeutic target in cancer therapy, with the tumor microenvironment (TME) playing a pivotal role in regulating ferroptosis. Although macrophages contribute to ferroptosis regulation within TME, the underlying mechanisms remain unclear. In this study, we demonstrate that macrophages consistently attenuate GPX4 inhibitor-induced lipid peroxidation and cell death in various tumor cell lines, whereas their resistance to cysteine transport inhibitor-triggered ferroptosis varies across cell types. This tumor protection from ferroptosis is mediated through macrophage-tumor cell contact and the delivery of macrophage-derived extracellular vesicles (Mφ-EV). Transcriptomic and proteomic analyses revealed that macrophages and Mφ-EV enhance glutathione metabolism in tumor cells. Notably, Mφ-EV are uniquely enriched with the glutathione metabolism-related protein PRDX6. Mechanistically, the glutathione peroxidase activity of PRDX6 elevates intracellular reduced glutathione, suppresses lipid peroxidation, and thereby mitigates ferroptosis. Furthermore, macrophage-derived PRDX6 reduces mitochondrial superoxide accumulation, alleviates ferroptosis-induced mitophagy, and enhances tumor cell viability, ultimately promoting tumor growth. Together, our findings provide a novel mechanism of ferroptosis resistance in TME, wherein macrophages confer tumor cell resilience by bypassing GPX4 inhibition.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103826"},"PeriodicalIF":11.9,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}