Redox Biology最新文献

{"title":"Supplementing sialic acid analogs overcomes radiotherapy resistance in triple-negative breast cancer by exacerbating ER stress","authors":"Muwen Yang ,&nbsp;Dongni Shi ,&nbsp;Jianbo Lyu ,&nbsp;Yibing Pan ,&nbsp;Yiyang Lyv ,&nbsp;Xiangfu Chen ,&nbsp;Ying Ouyang ,&nbsp;Yajie Liu ,&nbsp;Yue Li ,&nbsp;Libing Song","doi":"10.1016/j.redox.2025.103712","DOIUrl":"10.1016/j.redox.2025.103712","url":null,"abstract":"<div><div>Radiotherapy is a cornerstone treatment for triple-negative breast cancer (TNBC), and its incorporation has significantly delayed tumor recurrence. However, the emergence of radiotherapy resistance remains a major clinical challenge, substantially compromising treatment efficacy. Sialylation play a pivotal role in tumor therapeutic resistance which refers to the covalent linkage of sialic acids at the terminal ends of glycoproteins, a process catalyzed by a family of sialyltransferases. However, the function and mechanisms of sialylation in radiotherapy resistance remain elusive. In this study, upregulation of Galbeta1-4 GlcNAc alpha 2,3 sialyltransferase (ST3GAL4) was observed in association with sialylation in TNBC patients with radiotherapy resistance and predicted poorer survival. ST3GAL4 catalyzed α2,3-sialylation of HSP90B1, then facilitates its retrograde trafficking from the Golgi to ER mediated by SURF4 cargo receptor. ER-localized HSP90B1 accelerates the clearance of radiotherapy-induced misfolded proteins and upregulates the PERK-EIF2α-ATF4 pathway, which further transcriptionally upregulates antioxidant factors, such as SLC1A5, GCLC, and CTNS, to inhibit radiotherapy-induced ROS accumulation, ultimately leading to radiotherapy resistance, and poor clinical outcomes. Most importantly, sialic acid analogs (SAA) 3Fax-NeuAc inhibited the sialylation of HSP90B1 and its transport to the ER, thereby effectively overcomed radiotherapy resistance in TNBC. This study suggests that ST3GAL4 confers radiotherapy resistance through the induction of adaptive ER stress by sialylated HSP90B1, while the application of SAA provides a novel therapeutic option against radioresistance of TNBC.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103712"},"PeriodicalIF":10.7,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144253775","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":"LncRNA PVT1 promotes cuproptosis through transcriptional activation of FDX1 in colorectal cancer","authors":"Jinyan Ma ,&nbsp;Yingjie Zhang ,&nbsp;Zhuoran Sun ,&nbsp;Hui Guo ,&nbsp;Xiang Li ,&nbsp;Jueting Cai ,&nbsp;Meichen Zhang ,&nbsp;Mengmeng Chen ,&nbsp;Jingjing Jiang ,&nbsp;Lingling Zhang","doi":"10.1016/j.redox.2025.103722","DOIUrl":"10.1016/j.redox.2025.103722","url":null,"abstract":"<div><h3>Background</h3><div>Cuproptosis, a copper-dependent form of regulated cell death, has emerged as a redox-sensitive vulnerability in cancer. However, the molecular basis by which this process is initiated and sustained in tumors remains poorly defined.</div></div><div><h3>Methods</h3><div>We investigated the functional role of FDX1 in cuproptosis in colorectal cancer through a series of in <em>vivo</em> and in <em>vitro</em> assays. Differential gene expression analysis and correlation studies were employed to identify long noncoding RNAs (lncRNAs) that regulate FDX1. Techniques such as molecular docking simulations, chromatin isolation by RNA purification (ChIRP), chromatin immunoprecipitation (ChIP), luciferase reporter assays, and bioinformatics analysis have elucidated the interactions and mechanisms between PVT1 and FDX1. The therapeutic potential of the PVT1-FDX1 axis was evaluated in a mouse xenograft model.</div></div><div><h3>Results</h3><div>FDX1 is upregulated in colorectal cancer and is indispensable for cuproptosis both in <em>vitro</em> and in <em>vivo</em>. The cuproptosis-related lncRNA PVT1 acts as a novel upstream regulator of FDX1. Mechanistically, PVT1 directly binds to the FDX1 promoter, increasing H3K27ac deposition and activating FDX1 transcription. Our findings also revealed that 35/98 nt of PVT1 bind to the −104/-41 bp region of the FDX1 promoter. Additionally, PVT1 was found to recruit SF1 to the FDX1 promoter, further enhancing FDX1 expression, leading to proteotoxic stress and ultimately triggering copper-dependent cell death. Clinically, PVT1 increases tumor sensitivity to cuproptosis by promoting FDX1 transcription.</div></div><div><h3>Conclusions</h3><div>We identify a novel regulatory axis in which PVT1 promotes cuproptosis by epigenetically activating FDX1 in colorectal cancer. Targeting the PVT1-FDX1 axis may offer an effective anticancer strategy, particularly given the widespread overexpression of PVT1 and its role in therapy resistance.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103722"},"PeriodicalIF":10.7,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144263509","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":"TRPV2 channels facilitate pulmonary endothelial barrier recovery after ROS-induced permeability","authors":"Lena Schaller,&nbsp;Martina Kiefmann,&nbsp;Thomas Gudermann,&nbsp;Alexander Dietrich","doi":"10.1016/j.redox.2025.103720","DOIUrl":"10.1016/j.redox.2025.103720","url":null,"abstract":"<div><div>Reactive oxygen species (ROS), such as hydrogen peroxide (H₂O₂), are known signaling molecules that increase endothelial barrier permeability. In this study, we investigated the roles of redox-sensitive transient receptor potential (TRP) ion channels, TRPM2, TRPV2 and TRPV4, in H₂O₂-induced endothelial barrier dysfunction. Using primary human pulmonary microvascular endothelial cells (HPMEC), we employed impedance-based resistance measurements, Western blot, and immunofluorescence staining to assess the effects of H₂O₂ on the endothelial barrier. Exposure to sublytic concentrations of H₂O₂ caused an acute loss of endothelial barrier integrity, accompanied by the cleavage of vascular endothelial cadherin (VE-cadherin), which was also apparent after application of the TRPV2 activator cannabidiol. The inhibition of either TRPV2 with tranilast or a disintegrin and metalloprotease domain-containing protein 10 (ADAM10) with GI254023X significantly reduced H₂O₂-induced VE-cadherin cleavage, while TRPM2 inhibition by econazole significantly increased H₂O₂-driven VE-cadherin cleavage and blockage of TRPV4 showed no effect. Although inhibition of either TRPV2 or ADAM10 did not prevent the initial loss of barrier resistance upon H₂O₂ exposure, both were essential for the subsequent recovery of barrier integrity. Time-course immunofluorescence stainings revealed that HPMEC barrier recovery involved a transient localization of N-cadherin proteins at adherens junctions. This process of cadherin-switching did not occur upon inhibition of TRPV2 or ADAM10. Our results highlight a novel role for TRPV2 as a redox sensitive ion channels in the microvascular endothelium and provide insight into the mechanisms underlying pulmonary microvascular endothelial barrier recovery.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103720"},"PeriodicalIF":10.7,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144298623","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":"Immunomodulatory effects of 4-hydroxynonenal","authors":"Melina Ioannidis ,&nbsp;Johanna Tjepkema ,&nbsp;Michael R.P. Uitbeijerse ,&nbsp;Geert van den Bogaart","doi":"10.1016/j.redox.2025.103719","DOIUrl":"10.1016/j.redox.2025.103719","url":null,"abstract":"<div><div>The reactive aldehyde 4-hydroxy-2-nonenal (4-HNE) is a byproduct of lipid peroxidation driven by reactive oxygen species (ROS). 4-HNE covalently binds to macromolecules such as proteins, altering their functions. While 4-HNE is implicated in various ROS-related pathologies, its impact on the immune system remains incompletely understood. This review explores how 4-HNE influences molecular mechanisms involved in inflammation and immune cell functions. 4-HNE modulates inflammation through the interaction with several signaling pathways, including nuclear factor kappa-light-chain enhancement of activated B cells (NF-κB), nuclear factor erythroid 2-related factor (Nrf2), mitogen-activated protein kinases (MAPK), toll-like receptor (TLR) 4, and stimulator of interferon genes (STING), thereby affecting immune responses and modulating cytokine production and inflammasome activation. However, its effects are complex, exhibiting both pro- and anti-inflammatory properties depending on dose and cell type. This review highlights the multiple mechanisms by which 4-HNE modulates the immune cells' responses.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103719"},"PeriodicalIF":10.7,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144237327","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":"Phytochemical nanozymes reprogram redox for balanced antimicrobial and regenerative therapy in acute and chronic diabetic wounds","authors":"Yipeng Pang ,&nbsp;Fructueux Modeste Amona ,&nbsp;Xiaohan Chen ,&nbsp;Yuxin You ,&nbsp;Ziqi Sha ,&nbsp;Zilu Liu ,&nbsp;Jiamin Li ,&nbsp;Yi Liu ,&nbsp;Xingtang Fang ,&nbsp;Xi Chen","doi":"10.1016/j.redox.2025.103718","DOIUrl":"10.1016/j.redox.2025.103718","url":null,"abstract":"<div><div>Chronic diabetic wounds are characterized by persistent oxidative stress and microbial infections, leading to delayed healing and tissue repair. While elevated reactive oxygen species (ROS) levels can provide bactericidal effects, uncontrolled oxidative stress simultaneously impairs tissue regeneration. Thus, precise redox modulation that balances antimicrobial efficacy with tissue regeneration is critical for effective wound therapy. Herein, we developed a phytochemical nanozymes system by integrating ferulic acid (FA) with cerium oxide nanoparticles (CeO₂), enabling precise redox modulation to balance antimicrobial efficacy with tissue regeneration. Structural analysis confirmed the uniform dispersion and pH-responsive release of FA and Ce ions, facilitating targeted redox modulation. The FA-CeO₂ nanozymes exhibited potent antioxidant activity through Ce³⁺/Ce⁴⁺ cycling and FA-mediated radical scavenging, effectively mitigating oxidative stress while promoting bacterial clearance against <em>S. aureus</em> and <em>E. coli</em>. Furthermore, FA-CeO₂ significantly enhanced Nrf2/HO-1 pathway activation, leading to upregulated VEGF/CD31 expression, accelerated cell proliferation, and enhanced collagen deposition <em>in vitro</em>. <em>In vivo</em>, FA-CeO₂ facilitated wound closure, reduced bacterial burden, and improved tissue regeneration in acute and diabetic wound models, with minimal cytotoxicity and excellent biocompatibility. These findings highlight the critical role of precise redox modulation in balancing antibacterial and regenerative therapy, positioning phytochemical nanozymes as a dual-modality platform for effective wound therapy and advancing nanomedicine strategies targeting oxidative stress and tissue repair.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103718"},"PeriodicalIF":10.7,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144271779","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":"Long-term senolytic therapy with Dasatinib and Quercetin alleviates lipofuscin-dependent retinal degeneration in mice","authors":"Bo Yang ,&nbsp;Kunhuan Yang ,&nbsp;Ruitong Xi ,&nbsp;Shiying Li ,&nbsp;Jingmeng Chen ,&nbsp;Yalin Wu","doi":"10.1016/j.redox.2025.103716","DOIUrl":"10.1016/j.redox.2025.103716","url":null,"abstract":"<div><div>Dry age-related macular degeneration (AMD) is one of the common blinding eye diseases, with pathological hallmarks of lipofuscin accumulation, neuroretina atrophy and retinal pigment epithelium (RPE) degeneration. Currently, there are no effective interventions for dry AMD. Although there is already evidence suggesting a link between cellular senescence and age-related diseases, it is still unclear whether long-term senolytic therapy with Dasatinib and Quercetin (D + Q) can slow the progression of dry AMD and ultimately prevent retinal structural damage and function loss. Mice lacking the <em>Abca4</em> and <em>Rdh8</em> genes (<em>Abca4</em>^{<em>−/−</em>}<em>Rdh8</em>^{<em>−/−</em>} mice) are a preclinical model of dry AMD. In this study, we performed a 4-month senolytic therapy with D + Q on 4-month-old <em>Abca4</em>^{<em>−/−</em>}<em>Rdh8</em>^{<em>−/−</em>} mice. <em>Abca4</em>^{<em>−/−</em>}<em>Rdh8</em>^{<em>−/−</em>} mice at the age of 8 months showed obvious retinal degeneration, along with RPE senescence, lysosomal alkalinization, lipofuscin accumulation and oxidative stress. Importantly, the long-term D + Q regimen significantly alleviated the degeneration of retinal structures and function in 8-month-old <em>Abca4</em>^{<em>−/−</em>}<em>Rdh8</em>^{<em>−/−</em>} mice, and it effectively repressed cellular senescence, lysosomal alkalinization, lipofuscin accumulation and oxidative stress in the RPE. This study is the first to demonstrate the effect of long-term intervention with senolytics D + Q on dry AMD. Overall, these findings highlight the potential of long-term senolytic treatment as an intervention for dry AMD.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103716"},"PeriodicalIF":10.7,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144239636","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":"Sex-specific metabolic responses to high-fat diet in mice with NOX4 deficiency","authors":"Jacob M. Bond ,&nbsp;Martina Dzubanova ,&nbsp;Adele K. Addington ,&nbsp;Charles P. Najt ,&nbsp;Elizabeth R. Gilbert ,&nbsp;Michaela Tencerova ,&nbsp;Siobhan M. Craige","doi":"10.1016/j.redox.2025.103698","DOIUrl":"10.1016/j.redox.2025.103698","url":null,"abstract":"<div><div>Reactive oxygen species (ROS) are critical mediators of cellular signaling that regulate metabolic homeostasis, including lipid uptake, synthesis, and storage. NADPH oxidase 4 (NOX4), a significant enzymatic source of ROS, has been identified as a redox-sensitive regulator of glucose and lipid metabolism. However, its contribution to sex-specific metabolic regulation remains poorly defined. This study compared how NOX4 knock-out (NOX4 KO) shifted systemic and tissue-specific metabolic phenotypes between male and female mice fed with a high-fat diet (HFD) for 20-weeks. We observed that male NOX4 mice on HFD exhibited reduced adiposity, diminished liver lipid accumulation, and improved glucose and insulin tolerance compared to male WT mice on HFD. In contrast, female NOX4 KO mice developed increased adiposity and lipid accumulation in peripheral adipose depots, accompanied by impaired glucose tolerance. Gene expression profiling in skeletal muscle and liver revealed distinct, sex-specific patterns of changes in genes related to lipid uptake, synthesis, and storage, possibly implicating differential activation of PPAR signaling pathways supportive of <em>in vivo</em> data. These findings identify NOX4 as a central regulator of sexually dimorphic lipid metabolism, acting through redox-sensitive transcriptional networks to shape divergent metabolic responses to HFD.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103698"},"PeriodicalIF":10.7,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144279210","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":"Retraction notice to “Curcumin blunts epithelial-mesenchymal transition of hepatocytes to alleviate hepatic fibrosis through regulating oxidative stress and autophagy” [Redox Biology 36 (2020) 101600]","authors":"Desong Kong ,&nbsp;Zili Zhang ,&nbsp;Liping Chen ,&nbsp;Weifang Huang ,&nbsp;Feng Zhang ,&nbsp;Ling Wang ,&nbsp;Yu Wang ,&nbsp;Peng Cao ,&nbsp;Shizhong Zheng","doi":"10.1016/j.redox.2025.103690","DOIUrl":"10.1016/j.redox.2025.103690","url":null,"abstract":"","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"84 ","pages":"Article 103690"},"PeriodicalIF":10.7,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226430","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":"Nitric Oxide restricts iron availability and induces quorum sensing in Streptococcus pyogenes","authors":"Ian E. McIntire ,&nbsp;Venkatesan Kathiresan ,&nbsp;Brian Hoffman ,&nbsp;Jennifer Chang ,&nbsp;Michael J. Federle ,&nbsp;Douglas D. Thomas","doi":"10.1016/j.redox.2025.103699","DOIUrl":"10.1016/j.redox.2025.103699","url":null,"abstract":"<div><div>Nitric oxide (NO) is a free radical signaling molecule with multiple biological functions. As part of the innate immune system, NO has antimicrobial properties playing an important role in host defense. Mechanisms of NO cytotoxicity result from its ability to bind metals and inhibit enzyme function or by increasing nitrosative and oxidative stress within cells. One of the primary biological targets of NO is the chelatable iron pool (CIP) which is quantitatively converted to dinitrosyliron complexes (DNIC) when it reacts with NO. Despite the numerous purported mechanisms attributed to NO's bactericidal properties, DNIC formation and its ability to restrict iron bioavailability from pathogenic bacteria has not been directly tested. <em>Streptococcus pyogenes</em> is a human pathogen that causes a range of diseases spanning from pharyngitis and impetigo to soft tissue necrosis and toxic shock. <em>S. pyogenes</em> employs the Rgg2/Rgg3 quorum sensing (QS) system to regulate aspects of its virulence potential, including biofilm formation, lysozyme resistance, and modulation of host innate immune response. Previous studies found that iron and manganese restriction induced Rgg2/Rgg3 QS, leading us to test whether NO-dependent iron restriction mediated by DNIC formation was sufficient to induce QS and related iron-starvation phenotypes. Here, we demonstrate that DNIC are formed in <em>S. pyogenes</em> exposed to physiologically relevant NO concentrations. The DNIC are formed from the CIP, and formation led to a significant reduction in the CIP, which correlated to a concomitant activation of QS and iron-regulated gene expression. These studies are the first to demonstrate that restriction of iron bioavailability mediated by DNIC formation is a functional mechanism by which NO can regulate QS, gene expression, and cell growth in bacteria.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103699"},"PeriodicalIF":10.7,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144237365","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":"Radiation-induced upregulation of itaconate in macrophages promotes the radioresistance of non-small cell lung cancer by stabilizing NRF2 protein and suppressing immune response","authors":"Mengjie Che ,&nbsp;Wenwen Wei ,&nbsp;Xiao Yang ,&nbsp;Jinzi Liang ,&nbsp;Yan Li ,&nbsp;Ying Ye ,&nbsp;Yajie Sun ,&nbsp;Yan Hu ,&nbsp;Zhanjie Zhang ,&nbsp;You Qin ,&nbsp;Jing Huang ,&nbsp;Bian Wu ,&nbsp;Haibo Zhang ,&nbsp;Kunyu Yang ,&nbsp;Chao Wan ,&nbsp;Lu Wen","doi":"10.1016/j.redox.2025.103711","DOIUrl":"10.1016/j.redox.2025.103711","url":null,"abstract":"<div><div>Radioresistance is one of the important reasons for local recurrence and distant metastasis in non-small cell lung cancer (NSCLC). Itaconate primarily functions as an anti-inflammatory metabolite in macrophages, however, its role in radiotherapy remains to be explored. In this study, we demonstrated that radiation significantly increases itaconate in the tumor microenvironment (TME), which is produced by macrophages. Mechanistically, the NF-κB signaling pathway is rapidly activated in macrophages, which enhances the binding of P65 to the <em>Acod1</em> promoter region, leading to significantly increased secretion of itaconate. Excessive itaconate alleviates oxidative stress of NSCLC cell lines by stabilizing NRF2 protein. Notably, specifically knocking out <em>Acod1</em> on myeloid cells enhances the activation of the tumor immune microenvironment in response to radiotherapy, particularly increasing the infiltration and activation of CD8⁺ T cells. Therefore, we propose that targeting Acod1 could be an effective strategy to improve radiosensitivity in NSCLC.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103711"},"PeriodicalIF":10.7,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144231187","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}