Pub Date : 2026-01-23DOI: 10.1016/j.redox.2026.104041
Jonas Benjamim , Stephen J. Bailey , Leonardo da Silva Gonçalves , Mia Burleigh , Mario Siervo , Andrew R. Coggan , Raúl Bescos
Nitric oxide (NO) is a critical signalling molecule in cardiovascular, metabolic, and muscular function. Endogenous NO production occurs via two primary metabolic pathways: 1) the classical nitric oxide synthases (NOS) pathway, and 2) the alternative (nitrate–nitrite–NO) pathway, in which inorganic nitrate (NO3−) is sequentially reduced to nitrite (NO2−) and other NO intermediates (e.g., S-nitrosothiol). The latter pathway relies heavily on the oral microbiota, which catalyze the two-electron partial reduction of NO3− to NO2−, which is influenced by oral physiology, microbial composition and salivary flow. While the role of exercise training in enhancing NOS-derived NO is well established, emerging evidence suggests that it may also augment NO bioavailability through the NO3−–NO2-–NO pathway. Furthermore, exercise training may influence the composition and functionality of oral microbiota, thereby indirectly modulating NO metabolism and oral health. However, the synergistic effects of exercise and oral microbiota on NO production remain underexplored. This review synthesises current evidence on how physical exercise may modulate both NO pathways and discusses the broader physiological implications.
{"title":"Influence of exercise training on nitric oxide pathways and their physiological effects","authors":"Jonas Benjamim , Stephen J. Bailey , Leonardo da Silva Gonçalves , Mia Burleigh , Mario Siervo , Andrew R. Coggan , Raúl Bescos","doi":"10.1016/j.redox.2026.104041","DOIUrl":"10.1016/j.redox.2026.104041","url":null,"abstract":"<div><div>Nitric oxide (NO) is a critical signalling molecule in cardiovascular, metabolic, and muscular function. Endogenous NO production occurs via two primary metabolic pathways: 1) the classical nitric oxide synthases (NOS) pathway, and 2) the alternative (nitrate–nitrite–NO) pathway, in which inorganic nitrate (NO<sub>3</sub><sup>−</sup>) is sequentially reduced to nitrite (NO<sub>2</sub><sup>−</sup>) and other NO intermediates (e.g., S-nitrosothiol). The latter pathway relies heavily on the oral microbiota, which catalyze the two-electron partial reduction of NO<sub>3</sub><sup>−</sup> to NO<sub>2</sub><sup>−</sup>, which is influenced by oral physiology, microbial composition and salivary flow. While the role of exercise training in enhancing NOS-derived NO is well established, emerging evidence suggests that it may also augment NO bioavailability through the NO<sub>3</sub><sup>−</sup>–NO<sub>2</sub><sup>-</sup>–NO pathway. Furthermore, exercise training may influence the composition and functionality of oral microbiota, thereby indirectly modulating NO metabolism and oral health. However, the synergistic effects of exercise and oral microbiota on NO production remain underexplored. This review synthesises current evidence on how physical exercise may modulate both NO pathways and discusses the broader physiological implications.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104041"},"PeriodicalIF":11.9,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033551","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}
Pub Date : 2026-01-23DOI: 10.1016/j.redox.2026.104039
Ziqi Liu , Ruoxun Wang , Min Shen , Xinrui Lan , Weixing Yan , Sainan Wang , Mingfeng Jiang , Rongqing Li , Jie Zhao , Qicheng Wang , Xinyi Xv , Jingwen Zhou , Xin Pan , Wei Li , Weijuan Gong , Li Qian
The upstream mechanisms governing neuronal susceptibility to ferroptosis in Parkinson's disease (PD) remain incompletely defined. This study investigates the molecular pathways mediating dopaminergic neuron vulnerability to ferroptosis in PD. The Lymphocyte adaptor protein (LNK) is identified as an upstream regulator, with its expression being significantly increased in peripheral blood of PD patients and positively associating with motor impairment severity. Similar upregulation occurs in murine PD models, coinciding with enhanced neuronal susceptibility. LNK interacts with the E3 ubiquitin ligase casitas B-lineage lymphoma proto-oncogene (CBL), promoting nuclear translocation and K27-linked polyubiquitination-driven degradation of the RNA-binding protein heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1). As an N6-methyladenosine (m6A) reader, HNRNPA2B1 stabilizes GPX4 transcripts, and its depletion reduces GPX4 levels, impairing glutathione-dependent lipid peroxidation defense. A pharmacological screen identifies lifitegrast an FDA-approved ophthalmic LFA-1 antagonist, as a putative small molecule modulator capable of interacting with the LNK SH2 domain and attenuating LNK-associated signaling in cellular assays. In PD models, lifitegrast administration or genetic ablation of LNK was observed to mitigate dopaminergic neurodegeneration. These findings define the LNK–CBL–HNRNPA2B1–GPX4 axis in ferroptotic regulation and support LNK as a potential therapeutic target in PD.
{"title":"A LNK–CBL–HNRPA2B1–GPX4 signaling axis mediates dopaminergic neuron vulnerability to ferroptosis in Parkinson's disease","authors":"Ziqi Liu , Ruoxun Wang , Min Shen , Xinrui Lan , Weixing Yan , Sainan Wang , Mingfeng Jiang , Rongqing Li , Jie Zhao , Qicheng Wang , Xinyi Xv , Jingwen Zhou , Xin Pan , Wei Li , Weijuan Gong , Li Qian","doi":"10.1016/j.redox.2026.104039","DOIUrl":"10.1016/j.redox.2026.104039","url":null,"abstract":"<div><div>The upstream mechanisms governing neuronal susceptibility to ferroptosis in Parkinson's disease (PD) remain incompletely defined. This study investigates the molecular pathways mediating dopaminergic neuron vulnerability to ferroptosis in PD. The Lymphocyte adaptor protein (LNK) is identified as an upstream regulator, with its expression being significantly increased in peripheral blood of PD patients and positively associating with motor impairment severity. Similar upregulation occurs in murine PD models, coinciding with enhanced neuronal susceptibility. LNK interacts with the E3 ubiquitin ligase casitas B-lineage lymphoma proto-oncogene (CBL), promoting nuclear translocation and K27-linked polyubiquitination-driven degradation of the RNA-binding protein heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1). As an N6-methyladenosine (m6A) reader, HNRNPA2B1 stabilizes GPX4 transcripts, and its depletion reduces GPX4 levels, impairing glutathione-dependent lipid peroxidation defense. A pharmacological screen identifies lifitegrast an FDA-approved ophthalmic LFA-1 antagonist, as a putative small molecule modulator capable of interacting with the LNK SH2 domain and attenuating LNK-associated signaling in cellular assays. In PD models, lifitegrast administration or genetic ablation of LNK was observed to mitigate dopaminergic neurodegeneration. These findings define the LNK–CBL–HNRNPA2B1–GPX4 axis in ferroptotic regulation and support LNK as a potential therapeutic target in PD.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104039"},"PeriodicalIF":11.9,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033549","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}
Pub Date : 2026-01-23DOI: 10.1016/j.redox.2026.104048
Kangnan Zhang , Jinlu Han , Peng Chen , Hanhua Li , Yazhou Wu , Yingying Shi , Baohua Hou , Wenhao Weng , Yuehong Wang , Zhenhua Zhu
Chronic cadmium (Cd) exposure is increasingly associated with elevated cardiovascular disease (CVD) risk; however, the redox-dependent mechanisms underlying this association remain poorly defined. Epidemiological evidence indicates that frailty acts as a biological amplifier of Cd-related cardiovascular vulnerability, characterized by heightened oxidative stress, inflammation, and endothelial dysfunction. To elucidate these mechanisms, we focused on atherosclerosis—the pathological hallmark of CVD—and integrated population-based analyses with multi-omics approaches. Mendelian randomization confirmed a potential causal relationship between Cd exposure and CVD risk. Spatial and single-cell transcriptomic profiling of atherosclerotic tissues revealed that Cd exposure and frailty signatures were preferentially enriched within macrophage-dense regions exhibiting pronounced oxidative stress. Among macrophage subsets, the MP1 meta-program displayed the highest Cd- and frailty-associated gene scores and engaged in intense crosstalk with endothelial cells via the CXCL2/3/8–ACKR1 ligand–receptor axis (C-X-C motif chemokine ligand 2/3/8–atypical chemokine receptor 1). Mechanistically, Cd exposure reprogrammed macrophage metabolic and inflammatory states, driving excessive chemokine release and sustained ACKR1-dependent macrophage–endothelial interactions, which in turn promoted pathological accumulation of reactive oxygen species (ROS) and redox imbalance within atherosclerotic lesions. Importantly, blockade of ACKR1 markedly attenuated inflammatory signaling, reduced ROS accumulation, and alleviated vascular tissue injury. Collectively, these findings define a previously unrecognized Cd–frailty–ACKR1 redox-inflammatory axis that mechanistically links environmental metal exposure to oxidative vascular injury and highlights ACKR1 as a potential therapeutic target for mitigating pollution-associated cardiovascular disease.
{"title":"Integrative epidemiology and multi-omics reveal a frailty-associated ACKR1 redox axis linking cadmium exposure to atherosclerosis","authors":"Kangnan Zhang , Jinlu Han , Peng Chen , Hanhua Li , Yazhou Wu , Yingying Shi , Baohua Hou , Wenhao Weng , Yuehong Wang , Zhenhua Zhu","doi":"10.1016/j.redox.2026.104048","DOIUrl":"10.1016/j.redox.2026.104048","url":null,"abstract":"<div><div>Chronic cadmium (Cd) exposure is increasingly associated with elevated cardiovascular disease (CVD) risk; however, the redox-dependent mechanisms underlying this association remain poorly defined. Epidemiological evidence indicates that frailty acts as a biological amplifier of Cd-related cardiovascular vulnerability, characterized by heightened oxidative stress, inflammation, and endothelial dysfunction. To elucidate these mechanisms, we focused on atherosclerosis—the pathological hallmark of CVD—and integrated population-based analyses with multi-omics approaches. Mendelian randomization confirmed a potential causal relationship between Cd exposure and CVD risk. Spatial and single-cell transcriptomic profiling of atherosclerotic tissues revealed that Cd exposure and frailty signatures were preferentially enriched within macrophage-dense regions exhibiting pronounced oxidative stress. Among macrophage subsets, the MP1 meta-program displayed the highest Cd- and frailty-associated gene scores and engaged in intense crosstalk with endothelial cells via the CXCL2/3/8–ACKR1 ligand–receptor axis (C-X-C motif chemokine ligand 2/3/8–atypical chemokine receptor 1). Mechanistically, Cd exposure reprogrammed macrophage metabolic and inflammatory states, driving excessive chemokine release and sustained ACKR1-dependent macrophage–endothelial interactions, which in turn promoted pathological accumulation of reactive oxygen species (ROS) and redox imbalance within atherosclerotic lesions. Importantly, blockade of ACKR1 markedly attenuated inflammatory signaling, reduced ROS accumulation, and alleviated vascular tissue injury. Collectively, these findings define a previously unrecognized Cd–frailty–ACKR1 redox-inflammatory axis that mechanistically links environmental metal exposure to oxidative vascular injury and highlights ACKR1 as a potential therapeutic target for mitigating pollution-associated cardiovascular disease.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104048"},"PeriodicalIF":11.9,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048388","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}
Pub Date : 2026-01-22DOI: 10.1016/j.redox.2026.104045
Shan Hu , Manqi Yang , Tao Liu , Min Huang , Hao Ju , Zheyu Liu , Saeed Kashkooli , Mian Cheng , Gang Wu
Objective
Doxorubicin (DOX) is a highly effective anthracycline chemotherapy drug that is commonly used in clinical practice. Because of the accumulation of its drug concentration, their clinical use is associated with severe cardiotoxicity. Serine incorporator 2 (Serinc2) had been shown to play an important role in maintaining cell structure and function. Here, the main purpose of this study was to explore the effect of Serinc2 on doxorubicin-induced cardiotoxicity and its mechanism.
Methods
Global Serinc2 knockout (Serinc2-KO) and cardiac-specific Serinc2 overexpression mice received a single or repeated DOX injection to establish chronic cardiotoxicity. Cardiac function, oxidative damage, cell apoptosis, and mitochondrial profiles were evaluated. Transcriptome and co-immunoprecipitation analysis were used to screen the underlying molecular pathways. Neonatal rat ventricle cardiomyocytes (NRVMs) were cultured to elucidate the role and mechanism of Serinc2 in vitro.
Results
Our data revealed significantly down-regulated Serinc2 expression in DOX-induced mouse hearts and NRVMs. Serinc2-KO aggravated, while cardiac-specific Serinc2 overexpression alleviated DOX-related myocardial injury, oxidative damage, cell apoptosis, and mitochondrial damage. Mechanistically, Serinc2 deficiency resulted in the impairment of mitochondrial bioenergetics and oxidative phosphorylation in DOX cardiotoxicity. Proteomic profiling and interactome analyses revealed that Serinc2 interacted with STAT3 to increase its phosphorylation and nuclear accumulation, a key factor to regulate mitochondrial bioenergetics. Cardiac overexpression of Serinc2 improves mitochondrial bioenergetics in DOX cardiomyopathy both in vivo and in vitro.
Conclusion
Taken together, it can be concluded that Serinc2 can maintain mitochondrial dynamics and increase mitochondrial bioenergy generation by enhancing STAT3 phosphorylation activity, thereby alleviating oxidative stress, apoptotic responses, and improving doxorubicin-induced cardiac dysfunction.
{"title":"Serinc2-STAT3 protects against doxorubicin-induced cardiotoxicity via promoting mitochondrial bioenergetics","authors":"Shan Hu , Manqi Yang , Tao Liu , Min Huang , Hao Ju , Zheyu Liu , Saeed Kashkooli , Mian Cheng , Gang Wu","doi":"10.1016/j.redox.2026.104045","DOIUrl":"10.1016/j.redox.2026.104045","url":null,"abstract":"<div><h3>Objective</h3><div>Doxorubicin (DOX) is a highly effective anthracycline chemotherapy drug that is commonly used in clinical practice. Because of the accumulation of its drug concentration, their clinical use is associated with severe cardiotoxicity. Serine incorporator 2 (Serinc2) had been shown to play an important role in maintaining cell structure and function. Here, the main purpose of this study was to explore the effect of Serinc2 on doxorubicin-induced cardiotoxicity and its mechanism.</div></div><div><h3>Methods</h3><div>Global Serinc2 knockout (Serinc2-KO) and cardiac-specific Serinc2 overexpression mice received a single or repeated DOX injection to establish chronic cardiotoxicity. Cardiac function, oxidative damage, cell apoptosis, and mitochondrial profiles were evaluated. Transcriptome and co-immunoprecipitation analysis were used to screen the underlying molecular pathways. Neonatal rat ventricle cardiomyocytes (NRVMs) were cultured to elucidate the role and mechanism of Serinc2 in vitro.</div></div><div><h3>Results</h3><div>Our data revealed significantly down-regulated Serinc2 expression in DOX-induced mouse hearts and NRVMs. Serinc2-KO aggravated, while cardiac-specific Serinc2 overexpression alleviated DOX-related myocardial injury, oxidative damage, cell apoptosis, and mitochondrial damage. Mechanistically, Serinc2 deficiency resulted in the impairment of mitochondrial bioenergetics and oxidative phosphorylation in DOX cardiotoxicity. Proteomic profiling and interactome analyses revealed that Serinc2 interacted with STAT3 to increase its phosphorylation and nuclear accumulation, a key factor to regulate mitochondrial bioenergetics. Cardiac overexpression of Serinc2 improves mitochondrial bioenergetics in DOX cardiomyopathy both in vivo and in vitro.</div></div><div><h3>Conclusion</h3><div>Taken together, it can be concluded that Serinc2 can maintain mitochondrial dynamics and increase mitochondrial bioenergy generation by enhancing STAT3 phosphorylation activity, thereby alleviating oxidative stress, apoptotic responses, and improving doxorubicin-induced cardiac dysfunction.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104045"},"PeriodicalIF":11.9,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033553","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}
Pub Date : 2026-01-21DOI: 10.1016/j.redox.2026.104044
Nathan Ponzar , Anna Pagotto , Srija Bandyopadhayay , Marvin J. Meyers , Vincenzo De Filippis , Robert Flaumenhaft , Nicola Pozzi
Allosteric modulation is central to enzyme function and an attractive strategy for drug development. Protein Disulfide Isomerase (PDI), the prototypical thiol-isomerase, exemplifies this potential through its structural flexibility and involvement in neurodegeneration, cancer, and thromboinflammatory disorders such as sepsis, stroke, cancer-associated thrombosis, and antiphospholipid syndrome. PDI consists of four thioredoxin-like domains (a-b-b′-a′), with catalytic CGHC motifs in a and a′ domains and a ligand-binding pocket in the b′ domain. We previously reported that the b′-ligand bepristat 2a (Bep2a) inhibits PDI activity toward large macromolecular substrates while allosterically enhancing activity toward smaller physiological substrates such as GSSG and l-cystine. Here, we define the molecular, thermodynamic, and structural basis of this dual function. Bep2a features an indole ring with five substituents (R1–R5). Using mutagenesis and HDX-MS, we mapped the complex topology, identified five residues (F249, H256, I301, F304, I318) involved in binding, and uncovered a ligand-induced rearrangement of the left helix that acts as a dynamic gate controlling pocket accessibility, a previously unrecognized regulatory mechanism. AI-informed modeling, SAR analysis, and smFRET revealed that Bep2a′s indole core binds perpendicularly in the pocket, with the R1 hydroxyl forming a critical hydrogen bond with H256, which is essential for binding but not for allosteric activation. Conversely, the R4 amine projects outward, serving as a key allosteric site that engages the catalytic domains and promotes PDI compaction. These findings uncover fundamental principles of PDI allosteric regulation and provide a blueprint for optimizing existing ligands and designing new ones with defined functional outcomes.
{"title":"Molecular determinants of allosteric modulation of protein disulfide isomerase by small-molecule b′-ligands","authors":"Nathan Ponzar , Anna Pagotto , Srija Bandyopadhayay , Marvin J. Meyers , Vincenzo De Filippis , Robert Flaumenhaft , Nicola Pozzi","doi":"10.1016/j.redox.2026.104044","DOIUrl":"10.1016/j.redox.2026.104044","url":null,"abstract":"<div><div>Allosteric modulation is central to enzyme function and an attractive strategy for drug development. Protein Disulfide Isomerase (PDI), the prototypical thiol-isomerase, exemplifies this potential through its structural flexibility and involvement in neurodegeneration, cancer, and thromboinflammatory disorders such as sepsis, stroke, cancer-associated thrombosis, and antiphospholipid syndrome. PDI consists of four thioredoxin-like domains (<strong>a-b-b′-a′</strong>), with catalytic CGHC motifs in <strong>a</strong> and <strong>a′</strong> domains and a ligand-binding pocket in the <strong>b′</strong> domain. We previously reported that the <strong>b′</strong>-ligand bepristat 2a (Bep2a) inhibits PDI activity toward large macromolecular substrates while allosterically enhancing activity toward smaller physiological substrates such as GSSG and <span>l</span>-cystine. Here, we define the molecular, thermodynamic, and structural basis of this dual function. Bep2a features an indole ring with five substituents (R1–R5). Using mutagenesis and HDX-MS, we mapped the complex topology, identified five residues (F249, H256, I301, F304, I318) involved in binding, and uncovered a ligand-induced rearrangement of the left helix that acts as a dynamic gate controlling pocket accessibility, a previously unrecognized regulatory mechanism. AI-informed modeling, SAR analysis, and smFRET revealed that Bep2a′s indole core binds perpendicularly in the pocket, with the R1 hydroxyl forming a critical hydrogen bond with H256, which is essential for binding but not for allosteric activation. Conversely, the R4 amine projects outward, serving as a key allosteric site that engages the catalytic domains and promotes PDI compaction. These findings uncover fundamental principles of PDI allosteric regulation and provide a blueprint for optimizing existing ligands and designing new ones with defined functional outcomes.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104044"},"PeriodicalIF":11.9,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014508","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}
Pub Date : 2026-01-21DOI: 10.1016/j.redox.2026.104047
Naoufal Akla , Anes Boudah , Thierry Bertomeu , Andrew Chatr-aryamontri , Michel Desjarlais , Borhane Annabi
Green tea polyphenols, particularly epigallocatechin-3-gallate (EGCG), are widely recognized for their beneficial preventive effects against chronic diseases including cancer and obesity. These effects are traditionally attributed to EGCG's antioxidant, anti-inflammatory, and metabolic regulatory properties. In conditions characterized by persistent oxidative stress, the disrupted redox signaling further creates a unique vulnerability that EGCG may exploit through a dual redox mechanism. Emerging evidence therefore suggests that EGCG not only mitigates oxidative damage but could also induce selective pro-oxidant stress in cancer cells, enhancing its therapeutic potential. To investigate this duality, we performed a genome-wide CRISPR/Cas9 knockout screen to identify genetic determinants of EGCG sensitivity and resistance. Our chemogenomic analysis revealed that loss of key antioxidant genes, including PRDX1, CAT, GSS, GCLM, and GCLC, significantly heightened cellular susceptibility to EGCG and green tea extract (GTE), underscoring the critical role of glutathione biosynthesis and redox homeostasis in mediating cytotoxicity. In contrast, knockouts of Kelch-like ECH-associated Protein 1 (KEAP1) and peroxisome-associated PEX genes conferred resistance, implicating in part NRF2 (also known as nuclear factor erythroid-derived 2-like 2; NFE2L2) activation and peroxisomal reactive oxygen species clearance in protective responses. Comparative profiling with gallic acid (GA), which lacks EGCG's catechin structure, further highlighted the gallate moiety's contribution to glutathione-dependent antioxidant mechanisms. Altogether, these findings illuminate the complex redox biology of EGCG and identify novel genetic vulnerabilities that may be leveraged to enhance its anticancer efficacy, particularly in obesity-associated cancers. Clinically, this work could support the development of EGCG-based interventions tailored to individual redox profiles, offering a precise chemopreventive strategy for patients at high risk of malignancies driven by metabolic and oxidative dysregulation. Furthermore, the identification of new genetic markers of EGCG sensitivity and resistance may inform future exploration of patient stratification.
{"title":"CRISPR-based chemogenomic profiling reveals redox vulnerabilities to epigallocatechin-3-gallate and green tea polyphenol extract","authors":"Naoufal Akla , Anes Boudah , Thierry Bertomeu , Andrew Chatr-aryamontri , Michel Desjarlais , Borhane Annabi","doi":"10.1016/j.redox.2026.104047","DOIUrl":"10.1016/j.redox.2026.104047","url":null,"abstract":"<div><div>Green tea polyphenols, particularly epigallocatechin-3-gallate (EGCG), are widely recognized for their beneficial preventive effects against chronic diseases including cancer and obesity. These effects are traditionally attributed to EGCG's antioxidant, anti-inflammatory, and metabolic regulatory properties. In conditions characterized by persistent oxidative stress, the disrupted redox signaling further creates a unique vulnerability that EGCG may exploit through a dual redox mechanism. Emerging evidence therefore suggests that EGCG not only mitigates oxidative damage but could also induce selective pro-oxidant stress in cancer cells, enhancing its therapeutic potential. To investigate this duality, we performed a genome-wide CRISPR/Cas9 knockout screen to identify genetic determinants of EGCG sensitivity and resistance. Our chemogenomic analysis revealed that loss of key antioxidant genes, including <em>PRDX1</em>, <em>CAT</em>, <em>GSS</em>, <em>GCLM</em>, and <em>GCLC</em>, significantly heightened cellular susceptibility to EGCG and green tea extract (GTE), underscoring the critical role of glutathione biosynthesis and redox homeostasis in mediating cytotoxicity. In contrast, knockouts of Kelch-like ECH-associated Protein 1 (<em>KEAP1</em>) and peroxisome-associated <em>PEX</em> genes conferred resistance, implicating in part NRF2 (also known as nuclear factor erythroid-derived 2-like 2; NFE2L2) activation and peroxisomal reactive oxygen species clearance in protective responses. Comparative profiling with gallic acid (GA), which lacks EGCG's catechin structure, further highlighted the gallate moiety's contribution to glutathione-dependent antioxidant mechanisms. Altogether, these findings illuminate the complex redox biology of EGCG and identify novel genetic vulnerabilities that may be leveraged to enhance its anticancer efficacy, particularly in obesity-associated cancers. Clinically, this work could support the development of EGCG-based interventions tailored to individual redox profiles, offering a precise chemopreventive strategy for patients at high risk of malignancies driven by metabolic and oxidative dysregulation. Furthermore, the identification of new genetic markers of EGCG sensitivity and resistance may inform future exploration of patient stratification.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104047"},"PeriodicalIF":11.9,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033552","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}
Chronic nonbacterial prostatitis (CNP) is a prevalent and refractory urogenital disorder whose immunopathogenic mechanisms remain incompletely understood. Given that redox imbalance is increasingly recognized as a critical driver of chronic inflammation, this study systematically investigated the role of epithelial redox stress in immune regulation during CNP and its underlying molecular mechanisms. By integrating plasma cytokine profiling, bulk and single-cell transcriptomic analyses, and experimental autoimmune prostatitis (EAP) models, we identified epithelial-derived macrophage migration inhibitory factor (MIF) as a central mediator driving chronic prostatic inflammation. Mechanistically, inflammatory injury induced excessive accumulation of reactive oxygen species (ROS) in epithelial cells, which in turn activated the redox-responsive transcription factor ZNF24 to bind the MIF promoter and promote its transcription. Epithelial cell-derived MIF acted in a paracrine manner on CD74-expressing macrophages. Engagement of CD74 by MIF stabilized PKM2 expression, enhanced macrophage glycolytic reprogramming, promoted PKM2 nuclear translocation, and activated NF-κB-dependent transcriptional programs, thereby driving M1 macrophage polarization and proinflammatory cytokine production. Pharmacological interventions targeting distinct key nodes of this signaling pathway-including inhibition of MIF (ISO-1), blockade of CD74 (neutralizing antibodies), stabilization of PKM2 tetramers (DASA-58), and suppression of NF-κB (JSH-23)-significantly attenuated prostatic inflammation, restored mitochondrial homeostasis, and alleviated pelvic pain in vitro or in vivo. Collectively, these findings define an epithelial ROS-ZNF24-MIF-macrophage CD74-PKM2-NF-κB signaling axis, through which coordinated enhancement of glycolytic reprogramming and inflammatory signaling promotes M1 macrophage polarization and drives the initiation and progression of CNP. Moreover, multiple redox-sensitive nodes within this pathway represent promising therapeutic targets for precision immunomodulation in CNP.
{"title":"Epithelial redox stress programs macrophage immunometabolism through a ZNF24-MIF–NF–κB pathway in chronic nonbacterial prostatitis","authors":"Fei Zhang , Andong Zhang , Tong Meng , Xianhong Liu, Cheng Yang, Chaozhao Liang, Meng Zhang","doi":"10.1016/j.redox.2026.104042","DOIUrl":"10.1016/j.redox.2026.104042","url":null,"abstract":"<div><div>Chronic nonbacterial prostatitis (CNP) is a prevalent and refractory urogenital disorder whose immunopathogenic mechanisms remain incompletely understood. Given that redox imbalance is increasingly recognized as a critical driver of chronic inflammation, this study systematically investigated the role of epithelial redox stress in immune regulation during CNP and its underlying molecular mechanisms. By integrating plasma cytokine profiling, bulk and single-cell transcriptomic analyses, and experimental autoimmune prostatitis (EAP) models, we identified epithelial-derived macrophage migration inhibitory factor (MIF) as a central mediator driving chronic prostatic inflammation. Mechanistically, inflammatory injury induced excessive accumulation of reactive oxygen species (ROS) in epithelial cells, which in turn activated the redox-responsive transcription factor ZNF24 to bind the MIF promoter and promote its transcription. Epithelial cell-derived MIF acted in a paracrine manner on CD74-expressing macrophages. Engagement of CD74 by MIF stabilized PKM2 expression, enhanced macrophage glycolytic reprogramming, promoted PKM2 nuclear translocation, and activated NF-κB-dependent transcriptional programs, thereby driving M1 macrophage polarization and proinflammatory cytokine production. Pharmacological interventions targeting distinct key nodes of this signaling pathway-including inhibition of MIF (ISO-1), blockade of CD74 (neutralizing antibodies), stabilization of PKM2 tetramers (DASA-58), and suppression of NF-κB (JSH-23)-significantly attenuated prostatic inflammation, restored mitochondrial homeostasis, and alleviated pelvic pain <em>in vitro</em> or <em>in vivo</em>. Collectively, these findings define an epithelial ROS-ZNF24-MIF-macrophage CD74-PKM2-NF-κB signaling axis, through which coordinated enhancement of glycolytic reprogramming and inflammatory signaling promotes M1 macrophage polarization and drives the initiation and progression of CNP. Moreover, multiple redox-sensitive nodes within this pathway represent promising therapeutic targets for precision immunomodulation in CNP.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104042"},"PeriodicalIF":11.9,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014511","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}
Pub Date : 2026-01-19DOI: 10.1016/j.redox.2026.104040
Zhengyu Yu , Hua Lin , Jingran He , Linfeng Li , Zhongwang Wang , Kun Li , Ting Niu , Bingquan Qiu
Metabolic disorders mediated chimeric antigen receptor - T cell (CAR-T) exhaustion impaired cancer immunotherapy. Endogenous sulfur dioxide (SO2) derived from L-cysteine catalysis regulated immune cell functions. However, its role in CAR-T cell exhaustion remained unknown. In this study, we identified that SO2 accumulated in the bone marrow microenvironment of relapsed multiple myeloma patients inhibited CD8+ T cell and CAR-T cell infiltration and promoted a transcriptional profile consistent with functional exhaustion, leading to impaired antitumor immunity. Tumor cell derived SO2 altered mitochondrial morphology and disrupted mitochondrial membrane potential in CAR-T cells, accompanied by impaired cytokine secretion and loss of cytotoxic function. Mechanistically, SO2 enhanced interaction of dynamin-related protein 1 (DRP1) and voltage-dependent anion channel 1 and mitochondrial fission via DRP1 sulphenylation at cysteine 607 (Cys607), with abnormal increases in DRP1 GTPase activity, disrupting mitochondrial integrity. Site mutation of Cys607 in CAR-T cells abrogated DRP1 sulphenylation and restored mitochondrial structure and improves antitumor immunity. These findings define a novel redox-mediated mechanism of mitochondrial dysfunction in CAR-T cells exhaustion and identify the SO2-DRP1 axis as a potential therapeutic target to overcome metabolic exhaustion in CAR-T cell therapy.
{"title":"Multiple myeloma derived sulfur dioxide drives CAR-T cell exhaustion by inducing mitochondrial dysfunction","authors":"Zhengyu Yu , Hua Lin , Jingran He , Linfeng Li , Zhongwang Wang , Kun Li , Ting Niu , Bingquan Qiu","doi":"10.1016/j.redox.2026.104040","DOIUrl":"10.1016/j.redox.2026.104040","url":null,"abstract":"<div><div>Metabolic disorders mediated chimeric antigen receptor - T cell (CAR-T) exhaustion impaired cancer immunotherapy. Endogenous sulfur dioxide (SO<sub>2</sub>) derived from L-cysteine catalysis regulated immune cell functions. However, its role in CAR-T cell exhaustion remained unknown. In this study, we identified that SO<sub>2</sub> accumulated in the bone marrow microenvironment of relapsed multiple myeloma patients inhibited CD8<sup>+</sup> T cell and CAR-T cell infiltration and promoted a transcriptional profile consistent with functional exhaustion, leading to impaired antitumor immunity. Tumor cell derived SO<sub>2</sub> altered mitochondrial morphology and disrupted mitochondrial membrane potential in CAR-T cells, accompanied by impaired cytokine secretion and loss of cytotoxic function. Mechanistically, SO<sub>2</sub> enhanced interaction of dynamin-related protein 1 (DRP1) and voltage-dependent anion channel 1 and mitochondrial fission via DRP1 sulphenylation at cysteine 607 (Cys607), with abnormal increases in DRP1 GTPase activity, disrupting mitochondrial integrity. Site mutation of Cys607 in CAR-T cells abrogated DRP1 sulphenylation and restored mitochondrial structure and improves antitumor immunity. These findings define a novel redox-mediated mechanism of mitochondrial dysfunction in CAR-T cells exhaustion and identify the SO<sub>2</sub>-DRP1 axis as a potential therapeutic target to overcome metabolic exhaustion in CAR-T cell therapy.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104040"},"PeriodicalIF":11.9,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146000846","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}
Pub Date : 2026-01-19DOI: 10.1016/j.redox.2026.104037
Lionel Tarrago , Lise Molinelli , Maya Belghazi , Mathilde Tribout , David Lemaire , Pierre Legrand , Sandrine Grosse , David Pignol , Monique Sabaty , Thierry Tron , Pascal Arnoux
Copper is typically coordinated by histidine, cysteine, or methionine in proteins, and these residues are particularly sensitive to oxidation. However, it remains unclear whether copper-coordinating residues are more prone to oxidation than non-coordinating ones, and how their susceptibility changes between the apo and copper-bound states. The copper chaperone PcuC, important for cytochrome c oxidase assembly in bacteria, contains a canonical binding site composed of two histidines and two methionines (H51xnM63 × 22H86xM88), as well as a disordered C-terminal extension enriched in methionine and histidine. To quantify methionine oxidation sensitivity in both apo- and Cu-bound PcuC, we used a methionine-specific oxaziridine probe combined with mass spectrometry and compared labeling patterns to those generated by 18O-labeled hydrogen peroxide. We show that methionine residues display distinct oxidation sensitivities in the apoprotein, and that the oxaziridine reacts similarly to H218O2. Importantly, this probe enables quantification of methionine oxidation independently of hydroxyl radicals generated by copper-driven Fenton chemistry, which lacks residue specificity. In the copper-bound form, Cu binding strongly alters methionine reactivity, with a marked increase in oxidation of the coordinating Met63 and Met88. Structural analysis revealed that two copper ions occupy the canonical site, while the C-terminal extension does not contribute to coordination. Comparison of structural features and oxidation values showed that methionine sensitivity correlates with solvent exposure in the folded domain, but with local positive charge in the disordered region. These findings demonstrate that copper coordination modulates methionine oxidation, and that oxaziridine-based probes provide powerful tools for mapping oxidation sensitivity in (metallo)proteins.
{"title":"Quantitative mapping of methionine sensitivity to oxidation in the copper-bound PcuC chaperone","authors":"Lionel Tarrago , Lise Molinelli , Maya Belghazi , Mathilde Tribout , David Lemaire , Pierre Legrand , Sandrine Grosse , David Pignol , Monique Sabaty , Thierry Tron , Pascal Arnoux","doi":"10.1016/j.redox.2026.104037","DOIUrl":"10.1016/j.redox.2026.104037","url":null,"abstract":"<div><div>Copper is typically coordinated by histidine, cysteine, or methionine in proteins, and these residues are particularly sensitive to oxidation. However, it remains unclear whether copper-coordinating residues are more prone to oxidation than non-coordinating ones, and how their susceptibility changes between the apo and copper-bound states. The copper chaperone PcuC, important for cytochrome <em>c</em> oxidase assembly in bacteria, contains a canonical binding site composed of two histidines and two methionines (H51x<sub><em>n</em></sub>M63 × <sub><em>22</em></sub>H86xM88), as well as a disordered C-terminal extension enriched in methionine and histidine. To quantify methionine oxidation sensitivity in both apo- and Cu-bound PcuC, we used a methionine-specific oxaziridine probe combined with mass spectrometry and compared labeling patterns to those generated by <sup>18</sup>O-labeled hydrogen peroxide. We show that methionine residues display distinct oxidation sensitivities in the apoprotein, and that the oxaziridine reacts similarly to H<sub>2</sub><sup>18</sup>O<sub>2</sub>. Importantly, this probe enables quantification of methionine oxidation independently of hydroxyl radicals generated by copper-driven Fenton chemistry, which lacks residue specificity. In the copper-bound form, Cu binding strongly alters methionine reactivity, with a marked increase in oxidation of the coordinating Met63 and Met88. Structural analysis revealed that two copper ions occupy the canonical site, while the C-terminal extension does not contribute to coordination. Comparison of structural features and oxidation values showed that methionine sensitivity correlates with solvent exposure in the folded domain, but with local positive charge in the disordered region. These findings demonstrate that copper coordination modulates methionine oxidation, and that oxaziridine-based probes provide powerful tools for mapping oxidation sensitivity in (metallo)proteins.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104037"},"PeriodicalIF":11.9,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146000848","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}
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