Redox Biology最新文献

{"title":"Nuclear pore complex dysfunction drives TDP-43 pathology in ALS","authors":"O. Ramírez-Núñez ,&nbsp;S. Rico-Ríos ,&nbsp;P. Torres ,&nbsp;V. Ayala ,&nbsp;A. Fernàndez-Bernal ,&nbsp;M. Ceron-Codorniu ,&nbsp;P. Andrés-Benito ,&nbsp;A. Vinyals ,&nbsp;S. Maqsood ,&nbsp;I. Ferrer ,&nbsp;R. Pamplona ,&nbsp;M. Portero-Otin","doi":"10.1016/j.redox.2025.103824","DOIUrl":"10.1016/j.redox.2025.103824","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration and pathological aggregation of TDP-43. While protein misfolding and impaired autophagy are established features, accumulating evidence highlights the nuclear pore complex (NPC)as a vulnerable, redox-sensitive hub in ALS pathogenesis. Here, we show that selective loss of NPC components, particularly the scaffold proteins NUP107 and NUP93, and FG-repeat-containing components—is a consistent finding across ALS postmortem spinal cord, SOD1^G93A and TDP-43 mutant mouse models, and human cell systems.CRISPR-mediated depletion of NUP107 in human cells triggers hallmark features of ALS pathology, including cytoplasmic TDP-43 mislocalization, increased phosphorylation, and autophagy dysfunction. Conversely, TDP-43 knockdown perturbs NPC composition, suggesting a reciprocal regulatory loop. Crucially, we demonstrate that oxidative stress exacerbated NPC subunit mislocalization and enhanced TDP-43 aggregation. Using oxime blotting and DNPH assays, we show that FG-repeat subunits of NPC were direct targets of redox-driven carbonylation, indicating that oxidative modifications compromise NPC integrity thuspotentially affecting nucleocytoplasmic transport. Our findings established NPC dysfunction as a redox-sensitive driver of TDP-43 pathology in ALS and highlight nucleocytoplasmic transport as a promising therapeutic axis. The susceptibility of long-lived NPC proteins to oxidative damage provides a mechanistic link between redox stress, proteostasis collapse, and neurodegeneration.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103824"},"PeriodicalIF":11.9,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858436","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":"Quantum sensing of free radicals in macrophages reveals early autophagy-lysosome regulation in an atherosclerosis cell model","authors":"Siyu Fan ,&nbsp;Han Gao ,&nbsp;Wesley Nieuwhof ,&nbsp;Thomas Mulder ,&nbsp;Beatriz F.M. Fumelli ,&nbsp;Runrun Li ,&nbsp;Rokshana Sharmin ,&nbsp;Maria Niora ,&nbsp;Glaucia M. Machado-Santelli ,&nbsp;Kirstine Berg Sorensen ,&nbsp;Willy de Haan ,&nbsp;Hélder A. Santos ,&nbsp;Romana Schirhagl","doi":"10.1016/j.redox.2025.103825","DOIUrl":"10.1016/j.redox.2025.103825","url":null,"abstract":"<div><div>Atherosclerosis is the predominant cause of death in industrialized countries and is on track to become the foremost cause of death worldwide. Free radicals play a crucial role in regulating the degradation system in macrophages within plaques which lead to complications in atherosclerosis. They are linked to the decline of autophagy-lysosomes and plaque progression. However, their specific production sites and timing remain unclear. To investigate free radical production in the macrophage autophagy-lysosome system's response to stress, we employed nanodiamond-based quantum sensing. By incubating RAW 264.7 macrophages with nanodiamonds and oxidized low-density lipoprotein, we observed colocalization of nanodiamonds with oxLDL in the autophagy-lysosomal system. Quantum sensing was then applied to sense free radical production in the surrounding area. Our findings revealed a decrease in spin lattice relaxation (T1) times (more free radicals), with a 36.7 % and 31.8 % rise at 0.5 and 4 h of oxLDL incubation compared to controls. Additionally, we observed the nuclear translocation of transcriptional factor EB (TFEB), the master transcriptional regulator of autophagy-lysosomal biogenesis. This suggests the initiation of an autophagy-lysosomal program, which enhanced the cell's degradative capacity. Consequently, T1 values firstly increased after 1h. At 4h, a significant TFEB nuclear translocation was observed, leading to the increase of T1 values by 8.2 % and 20.3 % at 6 and 8 h, respectively, compared to the 4-h mark.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"87 ","pages":"Article 103825"},"PeriodicalIF":11.9,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145048149","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":"The protective role of adipogenic lineage precursors in maintaining bone marrow redox homeostasis in a mouse model of prenatal dexamethasone exposure","authors":"Jianwen Su ,&nbsp;Sushuang Ma ,&nbsp;Mankai Yang ,&nbsp;Jichang Wu ,&nbsp;Yijie Chen ,&nbsp;Mingchao Jin ,&nbsp;Qin Shi ,&nbsp;Xianrong Zhang","doi":"10.1016/j.redox.2025.103820","DOIUrl":"10.1016/j.redox.2025.103820","url":null,"abstract":"<div><div>Bone marrow adipogenic precursors play important roles in bone metabolism in both young and adult mice, but their contributions to early long bone development remains poorly understood. In this study, we elucidate the role of bone marrow adipocyte lineage precursors in modulating bone marrow redox homeostasis through the secretion of fibulin-5 (Fbln5), using a prenatal dexamethasone exposure (PDE) mouse model. Our previous research demonstrates that PDE induces cellular senescence in the bone marrow, resulting in long bone growth retardation in young offspring. Extending these findings, we now reveal that PDE not only induces cellular senescence and impairs bone formation, but also disrupts type H vessels and reduces Adiponectin-expressing (<em>Adipoq</em>^<em>+</em>) cells. Importantly, genetic ablation of <em>Adipoq</em>^<em>+</em> cells recapitulates the phenotypes observed in PDE-exposed offspring, characterized by increased cellular senescence and loss of osteoblasts and osteoprogenitors during the early postnatal period, ultimately resulting in reduced trabecular bone mass in young adult mice. RNA-seq and <em>in vivo</em> data identify that <em>Adipoq</em>^<em>+</em> cells are a primary source of Fbln5, and that PDE significantly reduced the number of <em>Adipoq</em>^<em>+</em> cells, thereby decreasing Fbln5 expression and elevating ROS stress in bone marrow. Moreover, targeted overexpression of Fbln5 in <em>Adipoq</em>^<em>+</em> cells via adeno-associated virus effectively mitigates cellular senescence and ROS accumulation, preserves type H vessels and osteoblasts, and normalizes osteoclasts activity, thereby rescuing the long bone growth retardation caused by PDE. Collectively, these findings uncover a previously unrecognized function of <em>Adipoq</em>^<em>+</em> cells in regulating redox homeostasis within the bone marrow microenvironment during the early stages of long bone development.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103820"},"PeriodicalIF":11.9,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144886633","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":"NRF2-dependent suppression of selenoprotein P expression promotes intracellular selenium metabolic remodeling and upregulation of antioxidant selenoproteins in hepatocellular carcinoma","authors":"Kotoko Arisawa ,&nbsp;Moeka Natori ,&nbsp;Tetta Hiranuma ,&nbsp;Misaki Shimizu ,&nbsp;Yuto Yamazaki ,&nbsp;Yasuhiro Miki ,&nbsp;Takashi Toyama ,&nbsp;Yoshiro Saito","doi":"10.1016/j.redox.2025.103821","DOIUrl":"10.1016/j.redox.2025.103821","url":null,"abstract":"<div><div>Selenium-containing antioxidant enzymes such as glutathione peroxidase 4 (GPx4) and thioredoxin reductase 1 (TrxR1, encoded by <em>TXNRD1</em>) have emerged as therapeutic targets in hepatocellular carcinoma (HCC), a highly treatment-resistant cancer. Hepatocytes play a central role in selenium metabolism by synthesizing and secreting selenoprotein P (SeP, encoded by <em>SELENOP</em>), the major selenium containing protein in plasma, which supplies selenium to peripheral tissues. Although decreased circulating SeP levels have been associated with HCC progression and poor prognosis, the underlying mechanisms remain unclear.</div><div>In this study, we reanalyzed publicly available single-cell RNA sequence data of HCC tumors and identified a distinct tumor cell cluster characterized by reduced <em>SELENOP</em> expression, enhanced <em>GPX4</em> and <em>TXNRD1</em> expression, and activation of NRF2 signaling. In HepG2 cells, pharmacological and genetic activation of NRF2 suppressed SeP expression, elevated TrxR1 levels, and promoted intracellular selenium accumulation. Consistently, SeP knockout (KO) cells exhibited increased intracellular selenium, upregulation of GPx1 and GPx4, and resistance to ferroptosis. Similarly, under selenium-deficient dietary conditions, SeP KO mice showed elevated hepatic selenium and GPx1 expression compared to wild-type controls.</div><div>These findings uncover a novel NRF2-mediated selenium metabolic remodeling mechanism in HCC, in which SeP suppression promotes intracellular selenium retention and selective upregulation of antioxidant selenoproteins. This redox adaptation contributes to ferroptosis resistance and may represent a potential therapeutic axis in liver cancer.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103821"},"PeriodicalIF":11.9,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144842530","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":"Rapamycin coated selenium nanoparticles relieve oxidative senescence of vascular endothelium by mitophagy","authors":"Yutian Zhang ,&nbsp;Jingru Wang ,&nbsp;Hui Yang ,&nbsp;Leting He ,&nbsp;Miao Cui ,&nbsp;Qinjie Ling ,&nbsp;Jingjun He ,&nbsp;Shan Gou ,&nbsp;Fei Liu ,&nbsp;Zhihui Cai ,&nbsp;Zhi Huang","doi":"10.1016/j.redox.2025.103822","DOIUrl":"10.1016/j.redox.2025.103822","url":null,"abstract":"<div><div>Rapamycin (RPM) extends longevity in various species and combats vascular senescence related diseases. Selenium nanoparticles (SeNPs) have attracted attention as a potential therapy for cardiovascular diseases due to their excellent antioxidant and drug-carrying capacity. However, RPM coated SeNPs (RPM-SeNPs) have not been reported and their potential for preventing endothelial oxidative senescence remains unclear. In the present study, RPM-SeNPs were generated by selenite and RPM with ascorbic acid reduction. Stability and dispersity of SeNPs were increased by coating with RPM, resulting in an average diameter of 67.51 ± 2.07 nm with a RPM:Se molar ratio of 1:120. Notably, RPM-SeNPs exhibited ameliorative effects on oxidative endothelial senescence in mouse aortas or MAECs induced by paraquat or hydrogen peroxide, respectively. There were evidenced by decreased SA-β-gal activity, lower SASP levels, and decreased endothelial dysfunction. Mechanically, RPM-SeNPs reduced oxidative stress in endothelial cells by upregulating GPX4, particularly mitochondrial GPX4 (mtGPX4) that mitigated of ROS and relieved mitochondria dysfunction. By downregulating the PI3K/Akt/mTOR pathway, RPM-SeNPs inhibited ULK1 phosphorylation at Ser757, subsequently leading to the activation of mitophagy and the reversal of mitochondrial dysfunction, including mitochondrial membrane potential collapse and ATP deficiency. Thus, these results suggest that RPM-SeNPs rescue endothelial cells from oxidative stress induced senescence by upregulating mtGPX4 and activating mitophagy. These results provide insight into the mechanisms of functionalizing SeNPs for potentially treating senescence-related diseases.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103822"},"PeriodicalIF":11.9,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858437","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":"Au(III) Schiff base complexes as oxidoreductase inhibitors against carbapenem- and colistin-resistant Gram-negative bacteria via targeting redox active motifs","authors":"Xiuli Chen ,&nbsp;Lin Lv ,&nbsp;Jianqiang Xu ,&nbsp;Jing Shi ,&nbsp;Xi Chen ,&nbsp;Guisha Zi ,&nbsp;Yuxuan Wu ,&nbsp;Shibo Sun ,&nbsp;Yufan Pang ,&nbsp;Qian Song ,&nbsp;Ling Ma ,&nbsp;Shuang Wei ,&nbsp;Tonghui Ma ,&nbsp;Wukun Liu","doi":"10.1016/j.redox.2025.103800","DOIUrl":"10.1016/j.redox.2025.103800","url":null,"abstract":"<div><div>Carbapenem- and colistin-resistant Gram-negative bacteria have become one of the most severe public health issues worldwide. The development of advanced antibacterial agents that can outpace microbial adaptation is imperative. The thioredoxin (Trx) and glutaredoxin (Grx) systems play important roles in maintaining redox homeostasis within Gram-negative bacterial cell membranes, with thioredoxin reductase (TrxR) and glutathione reductase (GR) being classical antibacterial targets. In this study, we found that Au(III) Schiff base complexes <strong>Au10</strong> and <strong>Au17</strong> exhibited potent activities against carbapenem- and colistin-resistant Gram-negative bacteria, as demonstrated in evaluations both in vitro and in vivo. Mechanistic studies revealed that <strong>Au10</strong> and <strong>Au17</strong> exert their antibacterial effects through multiple pathways: irreversibly inhibiting TrxR and GR activities via targeting redox-active motifs, impairing bacterial energy metabolism even at low concentrations, degrading deoxyribonucleic acid (DNA), causing reactive oxygen species (ROS) generation and intracellular redox imbalance. This study provides the first evidence that Au(III) Schiff base complexes possess strong activity against carbapenem- and colistin-resistant Gram-negative bacteria and can simultaneously inhibit the oxidoreductase in carbapenem- and colistin-resistant Gram-negative bacteria, establishing a new paradigm for antibacterial strategies and guiding future innovations in antibacterial therapy.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103800"},"PeriodicalIF":11.9,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925552","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":"Cisplatin-induced genetic alterations in KEAP1 promote therapeutic resistance in head and neck squamous cell carcinoma","authors":"Yuki Nakayama ,&nbsp;Keiko Taguchi ,&nbsp;Shun Wakamori ,&nbsp;Akira Uruno ,&nbsp;Akihito Otsuki ,&nbsp;Akira Ohkoshi ,&nbsp;Hidekazu Shirota ,&nbsp;Tomoyuki Iwasaki ,&nbsp;Yukio Katori ,&nbsp;Masayuki Yamamoto","doi":"10.1016/j.redox.2025.103819","DOIUrl":"10.1016/j.redox.2025.103819","url":null,"abstract":"<div><div>Cisplatin (CDDP) resistance remains a major challenge in the treatment of recurrent head and neck squamous cell carcinoma (HNSCC). The KEAP1-NRF2 system, a central regulator of cellular redox homeostasis, is frequently altered in cancer, but its contribution to acquired CDDP resistance in HNSCC remains to be clarified. To address this, we investigated NRF2 activation in CDDP resistance using seven parental (P) HNSCC cell lines and their CDDP-resistant (CR) derivatives. Among these P-CR pairs, three CR lines exhibited elevated NRF2 expression; two harbored <em>KEAP1</em> mutations, and one had an <em>NFE2L2</em> mutation that were present in both P and CR lines. These NRF2-high CR lines showed upregulation of NRF2 target genes and enrichment of xenobiotic metabolism and reactive oxygen species pathways. Mitomycin C (MMC), a cytotoxic agent for its synthetic lethality in NRF2-activated cancer cells, demonstrated strong cytotoxicity specifically in these NRF2-high CR lines. Immunohistochemical analysis on clinical samples found that high NRF2 expression was significantly associated with poor prognosis and was frequently observed in recurrent tumors following chemoradiotherapy with CDDP. These results suggest that CDDP therapy, while initially effective, may paradoxically promote tumor progression and therapeutic resistance by aberrantly activating the KEAP1-NRF2 axis. This redox-driven adaptation highlights a critical characteristic in NRF2-hyperactivated HNSCC that is exploitable by MMC treatment.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103819"},"PeriodicalIF":11.9,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144865039","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":"α-synuclein fibrils per se but not α-synuclein seeded aggregation causes mitochondrial dysfunction and cell death in human neurons","authors":"Plamena R. Angelova ,&nbsp;Noemi Esteras ,&nbsp;James Evans ,&nbsp;Marko Kostic ,&nbsp;Ronald Melki ,&nbsp;Jochen H.M. Prehn ,&nbsp;Sonia Gandhi ,&nbsp;Andrey Y. Abramov","doi":"10.1016/j.redox.2025.103817","DOIUrl":"10.1016/j.redox.2025.103817","url":null,"abstract":"<div><div>One of the major histopathological features of Parkinsons's disease – intracellular Lewy bodies - consists of misfolded α-synuclein. This protein can self-assemble, spread through the brain and seed its own aggregation. Aggregated α-synuclein is shown to induce mitochondrial dysfunction that leads to neuronal loss. Using human iPSC-derived SNCA triplication (3xSNCA) and isogenic control (ISO) neurons we studied whether acute exposure to fibrillar α-synuclein, or its seeding properties, induce effects on mitochondrial function and toxicity. Chronic exposure of neurons to fibrillar α-synuclein (up to 3 weeks) induces a gradual increase of endogenous α-synuclein seeding in neurons, with a decrease in the exogenous fibrillar α-synuclein in ISO and 3xSNCA neurons. Application of exogenous fibrillar α-synuclein induced mitochondrial depolarisation, impairment of complex I function, increased ROS production, oxidative stress and cell death. Notably, α-synuclein seeding following weeks of incubation almost completely restored mitochondrial function and redox balance of human neurons. Thus, mitochondrial dysfunction and oxidative stress in human neurons can be induced acutely only by transient exogenous fibrillar α-synuclein, but seeding is irrelevant to long-term mitochondrial dysfunction or toxicity. This study also indicates an acute, transient toxic insult followed by a remarkable period of adaptation and functional recovery, highlighting the resilience of human neurons.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103817"},"PeriodicalIF":11.9,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144829915","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":"DRP1 downregulation impairs mitophagy, driving mitochondrial ROS and SASP production in rheumatoid arthritis CD4+PD-1+T cells","authors":"Ziran Bai ,&nbsp;Jinyi Ren ,&nbsp;Jiaqing Liu ,&nbsp;Cheng Zhang ,&nbsp;Huina Huang ,&nbsp;Xiangge Zhao ,&nbsp;Xianmei Chen ,&nbsp;Jing Wei ,&nbsp;Jingjing Qi ,&nbsp;Siwen Yang ,&nbsp;Weiping Li ,&nbsp;Yawei Tang ,&nbsp;Guan Wang ,&nbsp;Xia Li","doi":"10.1016/j.redox.2025.103818","DOIUrl":"10.1016/j.redox.2025.103818","url":null,"abstract":"<div><div>T cell senescence occurs in patients with rheumatoid arthritis (RA), but the specific phenotype and its contribution to tissue-destructive inflammation remain unclear. Here, we aim to investigate whether PD-1 marks pathogenic senescent CD4⁺T cells and to explore the role and mechanism of senescent CD4⁺PD-1⁺T cells in RA pathogenesis. Here, we identified an expanded population of CD4⁺PD-1⁺T cells in RA patients that exhibited hallmark senescence features, including elevated senescence-associated secretory phenotype (SASP) production. Adoptive transfer experiments demonstrated that CD4⁺PD-1⁺T cells significantly accelerated disease progression in collagen-induced arthritis (CIA) models. Mechanistically, we demonstrated that RA CD4⁺PD-1⁺T cells showed decreased expression of dynamin-related protein 1 (DRP1) and impaired mitophagy, leading to mitochondrial reactive oxygen species (MtROS) accumulation and subsequent SASP production. Importantly, PD-1 signaling transcriptionally suppressed DRP1 expression through hypoxia inducible factor 1 alpha subunit (HIF-1α) inhibition. Our findings establish CD4⁺PD-1⁺T cells as a pathogenic senescent subset that drives RA progression through a PD-1-DRP1-mitophagy-SASP axis.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103818"},"PeriodicalIF":11.9,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858052","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":"Injectable ROS homeostasis protective hydrogel inhibiting microglial ferroptosis through the Nrf2/Slc7a11/Gpx4 to alleviate neuropathic pain and promote spinal cord injury repair","authors":"Lu Li ,&nbsp;Yu Cao ,&nbsp;Xiangsheng Zhang ,&nbsp;Jiayi Guo ,&nbsp;Ziqiang Lin ,&nbsp;Pengyu Zhou ,&nbsp;Chuyin Chen ,&nbsp;Jiahao Chen ,&nbsp;Yike Liu ,&nbsp;Danzhi Luo ,&nbsp;Jiurong Chen ,&nbsp;Yingdong Deng ,&nbsp;Peng Sun ,&nbsp;Zhiwen Zeng ,&nbsp;Jun Zhou","doi":"10.1016/j.redox.2025.103816","DOIUrl":"10.1016/j.redox.2025.103816","url":null,"abstract":"<div><div>Spinal cord injury (SCI) induced neuropathic pain (NP) remains a major clinical challenge due to persistent neuroinflammation and oxidative stress. We developed an injectable methacrylated and thiolated gelatin hydrogel loaded with quercetin (MSQ) to synergistically scavenge reactive oxygen species (ROS) and inhibit microglial ferroptosis for NP alleviation and neural repair. The MSQ hydrogel exhibited rapid photocrosslinking, sustained quercetin release, and robust ROS scavenging via thiol groups and quercetin, maintaining intracellular redox homeostasis. MSQ attenuated LPS-induced ferroptosis in BV2 microglia by upregulating Nrf2 expression, promoting its nuclear translocation, and activating the Slc7a11/Gpx4 pathway, thereby reducing lipid peroxidation and inflammatory cytokine release. Network pharmacology and molecular dynamics simulations confirmed quercetin's high-affinity binding to Nrf2. In a murine SCI model, MSQ implantation significantly reduced lesion area, suppressed microglial ferroptosis, and decreased pro-inflammatory mediators (TNFα, IL-1β, IL-6), while enhancing neuronal survival (Nissl/NeuN⁺ cells) and axonal regeneration (MAP2/5-HT⁺ expression). Motor functional recovery assays revealed improved BMS scores, gait regularity, and mechanical/thermal pain thresholds in MSQ-treated mice. This study highlights MSQ hydrogel as a multifunctional therapeutic platform that targets ROS homeostasis and microglial ferroptosis via the Nrf2/Slc7a11/Gpx4 axis, offering a promising strategy for post-SCI NP management and neural regeneration.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103816"},"PeriodicalIF":11.9,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144810143","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}