Redox Biology最新文献

{"title":"The electrophilic metabolite of kynurenine, kynurenine-CKA, requires C151 in Keap1 to derepress Nrf2","authors":"Jialin Feng ,&nbsp;Mara Carreño ,&nbsp;Hannah Jung ,&nbsp;Sharadha Dayalan Naidu ,&nbsp;Nicole Arroyo-Diaz ,&nbsp;Abel D. Ang ,&nbsp;Bhargavi Kulkarni ,&nbsp;Dorothy Kisielewski ,&nbsp;Takafumi Suzuki ,&nbsp;Masayuki Yamamoto ,&nbsp;John D. Hayes ,&nbsp;Tadashi Honda ,&nbsp;Landon Wilson ,&nbsp;Beatriz Leon-Ruiz ,&nbsp;Aimee L. Eggler ,&nbsp;Dario A. Vitturi ,&nbsp;Albena T. Dinkova-Kostova","doi":"10.1016/j.redox.2026.104009","DOIUrl":"10.1016/j.redox.2026.104009","url":null,"abstract":"<div><div>The Kelch-like ECH-associated protein 1/Nuclear factor-erythroid 2 p45-related factor 2 (Keap1/Nrf2) system responds to a wide array of structurally diverse small molecules, of both exogenous and endogenous origin, by inducing a robust cytoprotective program that allows adaptation during oxidative, metabolic and inflammatory stress. Here, we report that exposure to the tryptophan metabolite kynurenine and its electrophilic derivative kynurenine-carboxyketoalkene (Kyn-CKA) leads to an increase in the abundance of transcription factor Nrf2 and induction of Nrf2-target genes, including NAD(P)H:quinone oxidoreductase 1 (NQO1), in murine and human cells. Additionally, both kynurenine and Kyn-CKA activate the aryl hydrocarbon receptor (AhR). Using cellular thermal shift assays, we found that Kyn-CKA increases the thermal stability of Keap1-mCherry fusion protein, but not free mCherry, indicating target engagement of Keap1, the principal repressor of Nrf2. Critically, the ability of Kyn-CKA to increase the abundance of Nrf2 and expression of NQO1 in mouse embryonic fibroblasts (MEFs) expressing wild-type Keap1 was greatly diminished in C151S-Keap1 mutant MEFs. Furthermore, Kyn-CKA reacts with Keap1 C151 much faster <em>in vitro</em> than with the small molecule thiol <em>N</em>-acetyl cysteine, suggesting that Kyn-CKA is targeted to C151 by the surrounding active site. Experiments in wild-type, AhR-knockout, and Nrf2-knockout primary murine bone marrow-derived macrophages showed that Nrf2 is required for the acute anti-inflammatory activity of Kyn-CKA, whereas AhR is dispensable. Together, these findings demonstrate that Kyn-CKA requires C151 in Keap1 to derepress Nrf2 and reveal that Nrf2, but not AhR, is a main contributor to the anti-inflammatory activity of Kyn-CKA in macrophages.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104009"},"PeriodicalIF":11.9,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902650","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":"RIPK3-driven phosphorylation of MFN2 orchestrates endoplasmic reticulum-mitochondria interaction and cardiomyocyte stress responses","authors":"Yu Wang ,&nbsp;Tao Xu ,&nbsp;Qi Li ,&nbsp;Lin Ye ,&nbsp;Peiyan Wang ,&nbsp;Puhan Wang ,&nbsp;Yihan Song ,&nbsp;Xiang Ao ,&nbsp;Jianxun Wang ,&nbsp;Wei Ding","doi":"10.1016/j.redox.2026.104006","DOIUrl":"10.1016/j.redox.2026.104006","url":null,"abstract":"<div><h3>Background</h3><div>Recent studies have demonstrated that necroptosis is one of the main forms of cardiomyocyte death in heart diseases. However, the crosstalk between the death-receptor necroptosis pathway and the mitochondrial necroptosis pathway remains largely unknown. It has been reported that Mitofusin 2 (MFN2) can promote myocardial injury by inducing Endoplasmic Reticulum (ER)-mitochondria interaction. The purpose of this study was to investigate whether MFN2 promotes cardiac necroptosis and myocardial ischemia/reperfusion (I/R) injury by regulating ER-mitochondrial interactions, and whether this function of MFN2 can be regulated by the death-receptor necroptosis pathway.</div></div><div><h3>Methods</h3><div>Myocardial necroptosis was induced by H₂O₂ in H9c2 cardiomyocytes in vitro and through left anterior descending (LAD) ligation and subsequent reperfusion in C57/BL6 mice in vivo. ER-mitochondria interaction was detected by immunofluorescence. Calcium levels were analyzed by Rhod-AM staining. The interaction between MFN2 and Receptor-interacting protein kinase 3 (RIPK3) was explored by co-immunoprecipitation and immunofluorescence. The phosphorylation site of MFN2 was examined and measured via mass spectrometry analysis. Additionally, a customized MFN2 phosphorylation-specific antibody was used to detect the role of the Threonine 130 site of MFN2 in myocardial necroptosis. In vivo, MFN2 cardiac-specific knockout mice were constructed to further explore the effect of MFN2 on myocardial I/R injury and necroptosis.</div></div><div><h3>Results</h3><div>Our results showed that MFN2 participated in H₂O₂-induced cardiomyocyte necroptosis by promoting the formation of ER-mitochondrial interactions and ER-mitochondrial Ca²⁺ transfer, which could be regulated by RIPK3 via phosphorylating MFN2 at the Threonine 130 site. Moreover, mitochondrial Ca²⁺ overload induced mPTP opening and subsequent activation of Calpain1, resulting in the inhibition of mitophagy initiation. Both of these pathways could promote cardiac necroptosis. Furthermore, our results revealed that cardiac-specific knockout of MFN2 could attenuate myocardial I/R injury.</div></div><div><h3>Conclusion</h3><div>Our findings reveal that RIPK3 can mediate MFN2 phosphorylation to promote ER-mitochondria interaction and mitochondrial Ca²⁺ overload, leading to the induction of cardiac necroptosis.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104006"},"PeriodicalIF":11.9,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903372","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":"Tumor-intrinsic redox programming drives an SPP1-CD44 axis of immune suppression in uveal melanoma","authors":"Tongxin Ge ,&nbsp;Yun Yang ,&nbsp;Wenyue Zhang ,&nbsp;Mengyao Li ,&nbsp;Xiang Gu ,&nbsp;Ludi Yang ,&nbsp;Renbing Jia ,&nbsp;Xingyun Wang ,&nbsp;Xianqun Fan ,&nbsp;Ai Zhuang","doi":"10.1016/j.redox.2026.104011","DOIUrl":"10.1016/j.redox.2026.104011","url":null,"abstract":"<div><div>Uveal melanoma (UM) is a rare yet aggressive malignancy with a high propensity for distant metastasis and poor response to systemic therapies, including immunotherapies. Although recent single-cell studies have uncovered pronounced intratumoral heterogeneity and an immunosuppressive tumor microenvironment, the tumor-intrinsic metabolic programs that drive immune escape remain poorly defined. Here, we performed single-cell RNA sequencing on primary UM specimens to generate a high-resolution atlas of tumor and immune cell states. We identified a redox-optimized melanoma subpopulation under heavy metabolic-proteostatic demand, characterized by intensive protein secretory activity and elevated antioxidant defenses. This adaptive state is required to sustain the robust secretion of the matricellular protein SPP1, which suppressed the proliferation and function of CD8⁺ T cells through CD44 engagement. Disruption of redox equilibrium by enhancing reactive oxygen species (ROS) via a mitochondria-targeted oxidative phosphorylation inhibitor triggered endoplasmic reticulum stress and downregulated SPP1 expression, thereby defining a direct metabolic-immune regulatory axis. Together, our findings reveal a previously unrecognized ROS-SPP1-CD44 axis that links tumor redox homeostasis to immune evasion, providing mechanistic insight into the immune-resistant phenotype of UM and suggesting potential therapeutic vulnerabilities within the metabolic-immune crosstalk.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104011"},"PeriodicalIF":11.9,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957371","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":"Revisiting molecular hydrogen signaling in mitochondria: Is the Rieske protein the entry point or a downstream sentinel?","authors":"Sergej M. Ostojic","doi":"10.1016/j.redox.2026.104003","DOIUrl":"10.1016/j.redox.2026.104003","url":null,"abstract":"<div><div>A recent study published in <em>Redox Biology</em> (Volume 88, December 2025, 103952) demonstrates that molecular hydrogen (H₂) rapidly suppresses mitochondrial Complex III activity through a mechanism involving the Rieske iron-sulfur protein (RISP) and subsequent LONP1-dependent proteolysis, challenging the long-standing view of H₂ as merely a selective radical scavenger. While these findings compellingly identify RISP as a key mediator of mitochondrial responses to H₂, its designation as the primary molecular target warrants broader consideration. From an evolutionary and structural standpoint, RISP belongs to a wider family of hydrogenase-like mitochondrial redox proteins that retain ancient iron-sulfur architectures. Proteins such as succinate dehydrogenase subunit B (SDHB), iron-sulfur subunits of Complex I, and CISD family [2Fe–2S] proteins share comparable redox logic and strategic positioning within mitochondrial bioenergetic networks. Here, these candidates are prioritized and placed into a hierarchical, testable framework, and specific comparative structural, biochemical, and proteostatic approaches are proposed to define the true molecular entry point of H₂ signaling in human mitochondria.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 104003"},"PeriodicalIF":11.9,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903373","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":"Porcine epidemic diarrhea virus promotes viral replication via ROS/HIF-1α-mediated glycolysis","authors":"Yafang Xu ,&nbsp;Jinqiu Zhang ,&nbsp;Chengwei Yin ,&nbsp;Laizhen Liu ,&nbsp;Zhenglei Wang ,&nbsp;Shaodong Fu ,&nbsp;Rong Fan ,&nbsp;Yanyan Zhao ,&nbsp;Jinfeng Miao","doi":"10.1016/j.redox.2026.104008","DOIUrl":"10.1016/j.redox.2026.104008","url":null,"abstract":"<div><div>Porcine epidemic diarrhea virus (PEDV), a highly pathogenic coronavirus, causes recurrent outbreaks of severe enteric disease, posing a significant threat to the global swine industry. The persistent challenge highlights the urgent need for a deeper understanding of host-virus interactions to improve prevention and control strategies. Here, we demonstrated that PEDV infection reprogrammed host metabolism toward aerobic glycolysis, a metabolic shift that not only facilitated viral replication but also established an immunosuppressive microenvironment. PEDV infection activated the hypoxia-inducible factor-1α (HIF-1α) pathway and induced mitochondrial dysfunction, leading to the accumulation of mitochondrial reactive oxygen species (mROS), which in turn stabilized HIF-1α, creating a positive feedback loop that amplified glycolytic gene expression and lactate production. We confirmed that glycolysis was essential for PEDV replication, and that elevated glucose levels enhanced replication efficiency. Furthermore, PEDV-induced glycolysis and lactate accumulation inhibited the generation of interferons (IFNs), thereby facilitating immune evasion. Collectively, our findings revealed a metabolic-immune axis exploited by PEDV to optimize viral replication and subvert host defenses. This study not only provides novel insights into the metabolic adaptations underlying PEDV pathogenesis but also highlights host metabolic pathways as potential therapeutic targets to combat PEDV and other related coronaviruses.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 104008"},"PeriodicalIF":11.9,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902660","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":"Controlled release of coated antioxidants inhibits Citrobacter rodentium colonization in the colon of rats by reducing gut redox potential","authors":"Ni Feng ,&nbsp;Changsong Fu ,&nbsp;Jinwei You ,&nbsp;Dongfang Wang ,&nbsp;Xiaobo Feng ,&nbsp;Yong Su","doi":"10.1016/j.redox.2026.104005","DOIUrl":"10.1016/j.redox.2026.104005","url":null,"abstract":"<div><div>Intestinal redox potential serves as a critical parameter reflecting the dynamic characteristics of the gut microenvironment. To precisely modulate the intestinal redox potential and evaluate its inhibition of pathogenic colonization, this study built a controlled release system and further investigated its role in gut health under a lower redox potential. The results demonstrated that the controlled release formulation significantly reduced fecal redox potential more effectively than uncoated antioxidants. By optimizing the hydrodynamic size and zeta potential of ethoxyquin (EQ) and ferulic acid (FA), the coated FA formulation maintained high efficiency in reducing redox potential and reversed body weight loss induced by pathogenic infection. Both coated EQ (EQC) and FA (FAC) selectively enriched beneficial genera, such as <em>Lactobacillus</em> and <em>Limosilactobacillus</em>, while suppressing opportunistic pathogens like <em>Klebsiella</em>. Notably, coated FA demonstrated enhanced efficacy in alleviating <em>Citrobacter rodentium</em> (<em>C. rodentium</em>)-induced weight loss and reducing pathogens burden compared to uncoated FA. Mechanistically, coated FA promoted the enrichment of <em>Lactobacillus reuteri</em> (<em>L</em>. <em>reuteri)</em>, suppressed the proliferation of Enterobacteriaceae, and enhanced intestinal <em>Muc2</em> gene expression. Functional metagenomic analysis revealed that FAC significantly downregulated ABC transporter activity in Enterobacteriaceae, thereby impairing biofilm formation and synergizing with mucus secretion to inhibit pathogen colonization. Further <em>in vitro</em> co-culture trials confirmed that under a lower redox system, <em>L</em>. <em>reuteri</em> had a stronger inhibitory effect on <em>C. rodentium</em> as well as the expression of their virulence genes (<em>(tir, ler</em>). Collectively, these findings suggest that precise modulation of colonic redox potential through controlled release strategies represents a promising approach to enhance host defense against enteric pathogens via microbiota reprogramming.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 104005"},"PeriodicalIF":11.9,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145894323","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":"Macrophage AMPK activated by oxidative stress drives profibrotic crosstalk with tubular cells to accelerate renal fibrosis after ischemic and reperfusion injury","authors":"Yuandong Tao ,&nbsp;Min Zhang ,&nbsp;Lei Chen ,&nbsp;Hongshuai Jia ,&nbsp;Yunjie Yang ,&nbsp;Yangyang Wu ,&nbsp;Pin Li ,&nbsp;Zhuyuan Wen ,&nbsp;Xiaowei Zhang ,&nbsp;Xiangmei Chen ,&nbsp;Xizhao Chen ,&nbsp;Xiubin Li ,&nbsp;Huixia Zhou","doi":"10.1016/j.redox.2025.104002","DOIUrl":"10.1016/j.redox.2025.104002","url":null,"abstract":"<div><div>Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) that significantly increases the risk of progression to chronic kidney disease (CKD). Although oxidative stress has been implicated in this transition, the precise mechanisms through which it orchestrates inflammation and fibrosis during IRI-induced AKI-CKD progression remain poorly understood. In this study, we observed sustained reactive oxygen species (ROS) production in post-IRI kidneys. ROS were found to activate AMP-activated protein kinase (AMPK) in macrophages in a calcium-dependent manner. Conditional knockout of AMPKα1 in macrophages (<em>Lyz2</em>-Cre; <em>Prkaa1</em>-fl/fl mice) significantly attenuated renal fibrosis following IRI. Single-cell RNA sequencing analysis further revealed that AMPKα1 deletion reduced the accumulation of Arg1⁺ MMP12⁺ macrophages and diminished a profibrotic tubular epithelial cell (TEC) subpopulation marked by persistent expression of PDGFB and VCAM1. These macrophages were shown to interact with PDGFB⁺ VCAM1⁺ TECs. Mechanistically, macrophage-derived TWEAK signaling through its receptor Fn14 promoted PDGFB production in TECs, driving maladaptive changes and a fibrogenic phenotype. Importantly, TWEAK neutralization effectively mitigated the AKI-to-CKD transition. Together, our results identify macrophage AMPK as a key redox sensor that, upon activation by oxidative stress, initiates maladaptive macrophage-TEC crosstalk, ultimately promoting renal fibrosis and CKD progression.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104002"},"PeriodicalIF":11.9,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145894324","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104056"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146659368","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104063"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146659370","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104041"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146659378","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}