Antioxidants & redox signaling最新文献

{"title":"NINJ1 Aggravates Doxorubicin-Induced Cardiotoxicity by Suppressing AMPK-Mediated HIF-1α Deubiquitination.","authors":"Yankun Chen, Dan Yang, Yanghao Chen, Xi Jiang, Yalin Zeng, Peilin Xiao, Zhiyu Ling","doi":"10.1177/15230864261462524","DOIUrl":"10.1177/15230864261462524","url":null,"abstract":"<p><strong>Aims: </strong>Doxorubicin (DOX) remains a cornerstone of cancer therapy but is limited by dose-dependent cardiotoxicity with inadequate protective strategies. Nerve injury-induced protein 1 (NINJ1), a regulator of inflammation and cell death, has not been explored in this context. We sought to define the role of NINJ1 in DOX-induced cardiotoxicity and evaluate its translational potential.</p><p><strong>Results: </strong>Using complementary genetic, pharmacologic, and transcriptomic approaches, we demonstrate that NINJ1 is markedly upregulated in DOX-treated murine hearts and cardiomyocytes. Cardiomyocyte-specific NINJ1 deletion confers robust protection against cardiac dysfunction, oxidative stress, and apoptosis, whereas NINJ1 overexpression exacerbates injury. Mechanistically, NINJ1 suppresses AMP-activated protein kinase (AMPK) activation, promoting ubiquitin-mediated degradation of hypoxia-inducible factor-1α (HIF-1α), thereby impairing antioxidant gene programs. Multilevel evidence, including RNA sequencing, pathway enrichment, and gain- and loss-of-function models, establishes the NINJ1-AMPK-HIF-1α axis as a central regulator of redox homeostasis. Pharmacologic inhibition of NINJ1 with phenyl-β-D-glucopyranoside attenuates cardiac injury <i>in vivo</i> and <i>in vitro</i> without compromising DOX antitumor efficacy, supporting pathway specificity and therapeutic feasibility.</p><p><strong>Innovation: </strong>This study identifies NINJ1 as a previously unrecognized driver of anthracycline cardiotoxicity and uncovers a novel signaling axis linking membrane injury signaling to metabolic control of HIF-1α stability.</p><p><strong>Conclusions: </strong>NINJ1 promotes DOX-induced cardiotoxicity by destabilizing HIF-1α <i>via</i> AMPK inhibition. Targeting NINJ1 represents a promising cardioprotective strategy.</p><p><strong>Clinical significance: </strong>Therapeutic inhibition of NINJ1 protects the heart while preserving anticancer efficacy, offering a potential strategy to enhance the safety of anthracycline-based chemotherapy and improve outcomes in cancer patients. <i>Antioxid. Redox Signal.</i> 45, 435-455.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"435-455"},"PeriodicalIF":6.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Metabolic Memory to Ferroptotic Susceptibility: A Critical Review of Epigenetic Regulation and Ferroptosis in Diabetic Complications.","authors":"Hongjuan Fang, Qiang Wang","doi":"10.1177/15230864261466920","DOIUrl":"10.1177/15230864261466920","url":null,"abstract":"<p><strong>Background: </strong>The clinical phenomenon of metabolic memory, in which diabetic complications may progress despite later glycemic improvement, lacks a complete explanation. Persistent oxidative stress, advanced glycation, mitochondrial dysfunction, and epigenetic remodeling are established contributors, but how these processes intersect with regulated cell death programs is still unresolved.</p><p><strong>Main body: </strong>This review proposes and critically appraises the hypothesis that epigenetic dysregulation increases the susceptibility of diabetic tissues to ferroptosis. We employ the term \"epigenetic-ferroptosis link\" as an operational term denoting a potential mechanistic connection between hyperglycemia-associated chromatin/RNA-regulatory alterations and shifts in ferroptosis vulnerability. A key methodological tenet of our analysis is the clear demarcation between direct evidence from diabetic models and supportive mechanistic insights drawn from other pathological contexts, ensuring a rigorous assessment of the hypothesis against the available data.</p><p><strong>Conclusion: </strong>Ferroptosis is one execution pathway among several that can contribute to diabetic tissue injury. This framing highlights the critical importance of organ- and cell-type specificity, the experimental rigor required to conclusively demonstrate ferroptosis involvement, the inherent limitations of extracellular-vesicle biomarkers and epigenetic-editing approaches, and the validation steps that remain necessary before any clinical translation can be contemplated. <i>Antioxid. Redox Signal.</i> 45, 534-554.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"534-554"},"PeriodicalIF":6.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammation Impairs Poststroke Recovery by Disrupting Iron Homeostasis in Brain.","authors":"Xin Guo, Xiaofang Jin, Shaomeng Kang, Yingying Han, Qiaoya Zhao, Lihui Wu, Xintong Shi, Jingsi Meng, Peng Yu, Guofen Gao, Fudi Wang, Kang Han, Yan-Zhong Chang","doi":"10.1177/15230864261464407","DOIUrl":"10.1177/15230864261464407","url":null,"abstract":"<p><strong>Aim: </strong>The activation of microglia triggers an inflammatory response, which is frequently associated with an imbalance of iron metabolism. This study aimed to determine whether inflammation-associated iron dyshomeostasis contributes to impaired poststroke recovery and to explore the underlying mechanisms.</p><p><strong>Results: </strong>Ferroportin 1 (FPN1) deficiency in neurons and glial cells delayed sensorimotor function recovery following cerebral ischemia. FPN1 deficiency was associated with aggravated neuronal injury, enhanced apoptosis- and necroptosis-associated signaling, impaired myelin- and synapse-related repair, and reduced dendritic spine density in the ischemic cortex. Histological analyses, including hematoxylin and eosin staining and Nissl staining, further supported more severe peri-infarct pathological damage in <i>Fpn1^Nestin</i>-CKO mice. In addition, increased IgG extravasation indicated aggravated blood-brain barrier (BBB) disruption and secondary neurovascular injury after stroke. These pathological changes were accompanied by increased iron accumulation in the ischemic cortex and altered expression of iron metabolism-related molecules. Elevated inflammatory cytokine expression and increased hepcidin levels were associated with disrupted brain iron homeostasis in <i>Fpn1^Nestin</i>-CKO mice. Inhibition of JAK-STAT signaling with AG490 reduced p-STAT3 and hepcidin levels and was associated with modulation of iron-related and repair-associated responses, with more pronounced effects observed in <i>Fpn1</i>-deficient mice.</p><p><strong>Innovation and conclusion: </strong>These findings highlight a close association between inflammatory signaling, BBB dysfunction, and iron dyshomeostasis during poststroke recovery. Our results suggest that delayed sensorimotor recovery in mice with neuronal and glial FPN1 deficiency may be linked to inflammation-associated BBB disruption and subsequent iron accumulation in the ischemic brain. <i>Antioxid. Redox Signal.</i> 45, 417-434.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"417-434"},"PeriodicalIF":6.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148350324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Itaconate Ameliorates Skin Fibrosis Through Inhibition of HIF-1α/LDHA-Driven Aerobic Glycolysis.","authors":"Linxiao Li, Xiaohui Miao, Yu Cheng, Yingying Zhuang, Wuyan Lu, Yishu Lu, Yu Jiang, Zihao Hu, Jinyi Deng, Fengting Niu, Guangpeng Liu, Lei Cui, Shuaijun Li, Jiefeng Huang","doi":"10.1177/15230864261467594","DOIUrl":"10.1177/15230864261467594","url":null,"abstract":"<p><strong>Background: </strong>Skin fibrosis is a hallmark of scleroderma and other fibrotic skin disorders, yet effective therapies remain limited. Immune-derived metabolites have emerged as regulators of inflammation and tissue remodeling, but whether metabolic reprogramming within dermal fibroblasts contributes to skin fibrosis remains unclear.</p><p><strong>Methods: </strong>Human fibrotic skin samples, a bleomycin-induced mouse model, and primary dermal fibroblasts were used to investigate the role of immune-responsive gene 1 (<i>Irg1</i>) and its metabolic product itaconate. Transcriptomic analyses, metabolic profiling, pharmacologic modulation, and genetic perturbation were employed to define downstream signaling mechanisms.</p><p><strong>Key findings: </strong><i>Irg1</i> expression and endogenous itaconate levels were reduced in fibrotic human and murine skin. Restoration of itaconate significantly attenuated dermal thickening, collagen deposition, and fibroblast activation. Mechanistically, itaconate suppressed glycolytic reprogramming in activated fibroblasts, as evidenced by reduced glucose uptake, lactate production, and glycolytic enzyme expression. This metabolic effect was associated with inhibition of the Akt/GSK-3β pathway, destabilization of hypoxia-inducible factor 1α (HIF-1α), and subsequent downregulation of lactate dehydrogenase A (LDHA) transcription. Genetic or pharmacologic interference with HIF-1α or LDHA partially phenocopied itaconate's antifibrotic effects, supporting a functional link between itaconate signaling, fibroblast metabolism, and fibrotic progression.</p><p><strong>Conclusions: </strong>This study identifies loss of Irg1-itaconate signaling as a previously unrecognized driver of fibroblast metabolic reprogramming in skin fibrosis. By revealing a fibroblast-intrinsic, metabolism-centered mechanism linking immunometabolite deficiency to extracellular matrix overproduction, these findings extend itaconate's scope beyond immune regulation and highlight metabolic targeting of fibroblasts as a promising therapeutic strategy for fibrotic skin disease. <i>Antioxid. Redox Signal</i>. 45, 512-533.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"512-533"},"PeriodicalIF":6.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histone Lactylation Links Glycolysis to Ferroptosis in Diabetic Cataract.","authors":"Dan Tao, He Wang, Zeyuan Liu, Yonggang Wang, Linhong Lei, Shuo Li, Ruixi Li, Ninghua Ni","doi":"10.1177/15230864261463738","DOIUrl":"10.1177/15230864261463738","url":null,"abstract":"<p><strong>Aims: </strong>This study aimed to delineate a novel mechanistic axis linking hyperglycemia-driven glycolytic reprogramming to ferroptotic death in lens epithelial cells (LECs) and to determine its therapeutic significance in diabetic cataract (DC). Specifically, we sought to define the integration of metabolic, epigenetic (histone lactylation), and post-translational (fucosylation) pathways in DC pathogenesis.</p><p><strong>Results: </strong>Under hyperglycemic conditions, LECs exhibited robust glycolytic activation and lactate accumulation. This metabolic shift drove selective histone H3K18 lactylation at the promoter of theTSTA3 gene, leading to its increased transcription. The upregulated TSTA3 protein then promoted the core fucosylation of the NF-κB p50 subunit, which facilitated its nuclear translocation. Inside the nucleus, p50 transcriptionally activatedNOX1, resulting in excessive reactive oxygen species (ROS) production and subsequent ferroptotic cell death. Critically, both pharmacological inhibition of glycolysis and genetic silencing ofTSTA3 effectively attenuated oxidative stress, restored redox balance, and ameliorated cataract severity in a diabetic rat model.</p><p><strong>Innovation: </strong>This work identifies a previously unrecognized pathogenic cascade-the glycolysis-histone lactylation-fucosylation-ferroptosis axis-that directly links metabolic flux to epigenetic and signaling control in DC. By positioning TSTA3 as a central, druggable node within this axis, our study redefines cataract pathogenesis beyond simple oxidative damage, integrating multiple layers of cellular regulation.</p><p><strong>Conclusion: </strong>The glycolysis-histone lactylation-TSTA3-fucosylation-NOX1-ferroptosis axis is a critical driver of LEC death in diabetic cataract. Targeting this newly defined pathway, particularly the TSTA3 node, offers novel opportunities for mechanism-based therapeutic interventions and biomarker development, with potential implications for other complications of metabolic disease. <i>Antioxid. Redox Signal.</i> 45, 474-490.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"474-490"},"PeriodicalIF":6.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148343800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into the Multifaceted Roles of 3-Mercaptopyruvate Sulfurtransferase in Liver Diseases.","authors":"Yirong Xia, Meng Li","doi":"10.1177/15230864261464328","DOIUrl":"10.1177/15230864261464328","url":null,"abstract":"<p><strong>Significance: </strong>Hydrogen sulfide (H₂S), a vital gasotransmitter in liver physiology and pathology, is produced by cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (MPST). Although CSE and CBS have been extensively studied in liver diseases, the role of MPST has received less attention, despite its significant and complex regulatory functions in hepatic biology and metabolism.</p><p><strong>Recent advances: </strong>The involvement of MPST in antioxidant processes, mitochondrial function, and protein persulfidation highlights its multifaceted role in various liver diseases, where it can act either as a protective factor or as a contributor to disease progression, primarily through H₂S metabolism. Notably, MPST also participates in crosstalk between various organs, including adipose-liver, gut-liver, skeletal muscle-liver, and pancreas-liver interactions. We also summarize current genetic models and pharmacological modulators targeting MPST. This review highlights the importance of advancing our understanding of the MPST/H₂S pathway to develop promising therapeutic strategies for liver diseases.</p><p><strong>Critical issues: </strong>Current research focuses mainly on changes in the expression of MPST in liver diseases, but its underlying mechanisms require further elucidation. The available genetic and pharmacological tools are still limited, underscoring the need for specific modulators and tissue- or cell-specific conditional MPST knockout or knock-in models to advance future investigations.</p><p><strong>Future directions: </strong>Future research should focus on delineating stage-specific and cell type-dependent mechanisms of MPST in liver diseases, identifying upstream regulators, and elucidating detailed downstream molecular pathways mediating the effects of MPST. Ultimately, these efforts should aim to establish the clinical significance of MPST as a translational target. <i>Antioxid. Redox Signal.</i> 45, 491-511.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"491-511"},"PeriodicalIF":6.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148325745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolite Regulation of Mitochondrial Quality Control and Regulated Cell Death.","authors":"Jingjiang Hu, Chenbei Hu, Yaru Chen, Haihua Chen, Hongzhi Ouyang, Huaiqing Luo, Yufei Li, Xiaoning Peng, Ye Fan, Yongguang Tao, Li Xie, Li Cong, Xing Yu, Yiqun Jiang","doi":"10.1177/15230864261490413","DOIUrl":"https://doi.org/10.1177/15230864261490413","url":null,"abstract":"<p><strong>Background: </strong>Altered metabolism contributes to disease progression and variable treatment response, but metabolite abundance alone rarely determines whether stressed cells recover or undergo regulated cell death (RCD).</p><p><strong>Scope of review: </strong>This review proposes mitochondrial quality control (MQC) as an intermediate gating layer that links metabolic signals to cell-fate execution through coordinated redox control, mitochondrial integrity, organelle turnover, and renewal. Four representative metabolites-β-hydroxybutyrate (β-BHB), lactate, succinate, and acetate-span complementary substrate-, receptor-, redox-, and acylation-dependent mechanisms and illustrate how distinct metabolic inputs converge on different MQC nodes.</p><p><strong>Major conclusions: </strong>This framework explains why the same metabolite may support adaptation in one tissue or exposure window yet lower the death threshold in another. It predicts that tissue-specific flux and functional MQC reserve will outperform bulk metabolite abundance in forecasting RCD responses, that disrupting and rescuing the dominant MQC node will, respectively, abolish and restore a metabolite-dependent death phenotype, and that MQC changes will precede modality-specific execution events.Translational Outlook:Clinically, this predominantly preclinical framework can now be tested through mechanism-enriched trials that integrate metabolite exposure, metabolic competence, mitochondrial target engagement, and RCD output, providing a practical route for causal validation in humans. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"15230864261490413"},"PeriodicalIF":6.8,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149057277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Unified Mechanistic Framework for Copper Toxicity in Neutrophils: Metabolic Rewiring, Cell-Death Crosstalk, and Immune Dysfunction.","authors":"Rui Shi, Siyue Chen, Tingting Chen, Tongyu Zhu, Cheng Yang","doi":"10.1177/15230864261489976","DOIUrl":"https://doi.org/10.1177/15230864261489976","url":null,"abstract":"<p><strong>Significance: </strong>Copper is an essential redox-active micronutrient, but failure of copper compartmentalization can convert it from a catalytic cofactor into a source of oxidative, proteotoxic, and mitochondrial stress. Neutrophils are a plausible target of this transition because their antimicrobial functions depend on tightly organized redox reactions, whereas their short lifespan and limited biosynthetic reserve may restrict adaptation to metal stress.</p><p><strong>Recent advances: </strong>This review develops a unified framework in which copper dyshomeostasis first reshapes intracellular copper pools, antioxidant buffering, reduced nicotinamide adenine dinucleotide phosphate-dependent redox metabolism, and mitochondrial signaling; these metabolic disturbances then lower the threshold for several copper-associated cell-death programs; and the combined lesions alter granulopoiesis, chemotaxis, phagocytic killing, neutrophil extracellular trap formation, survival, and inflammatory resolution. Canonical ferredoxin 1-dihydrolipoamide <i>S</i>-acetyltransferase-dependent cuproptosis is treated as a testable, but not yet established, mechanism in mature neutrophils. Stronger evidence supports a broader spectrum of copper-induced injury that includes mitochondrial apoptosis, inflammasome-associated pyroptotic signaling, lipid peroxidation with ferroptosis-like features, and dysregulated neutrophil extracellular trap formation (NETosis).</p><p><strong>Critical issues: </strong>The inflammatory outcome of neutrophil death cannot be inferred from cell loss alone: Efficiently cleared apoptotic or early ferroptotic cells may contract the functional neutrophil pool, whereas lytic death, late membrane rupture, defective efferocytosis, and release of oxidized lipids, chromatin, histones, or granular proteins may amplify local inflammation.</p><p><strong>Future directions: </strong>By tracing individual routes from copper-pool disruption to defined cellular and tissue-level outcomes, this model distinguishes systemic copper overload from inflammatory copper redistribution and identifies the measurements required to establish copper-dependent neutrophil pathology in human disease. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"15230864261489976"},"PeriodicalIF":6.8,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149011912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond Cys65: Redox Effector Factor-1 CRISPR-Engineered Cys93 and Cys99 Mutants Reveal Cooperative and Secondary Roles of Redox Signaling and Pancreatic Ductal Adenocarcinoma Progression.","authors":"Sanya Haiaty, Jessica A Occhiuto, Eyram Kpenu, Randall S Wireman, Mahmut Mijit, Silpa Gampala, Dana K Mitchell, Xiao Wang, Akanksha Sharma, Rajesh Sardar, Jacqueline Peil, Chi Zhang, Mark R Kelley, Melissa L Fishel","doi":"10.1177/15230864261489484","DOIUrl":"https://doi.org/10.1177/15230864261489484","url":null,"abstract":"<p><strong>Aims: </strong>Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional protein implicated in pancreatic ductal adenocarcinoma (PDAC) through its redox regulation of oncogenic transcription factors (TFs) such as hypoxia-inducible factor 1-alpha, nuclear factor kappa-light-chain-enhancer of activated B cells, and others. While Cys65 is recognized as the primary redox-active residue, the functions of other cysteines remain only partially understood. Here, we describe the first CRISPR-engineered homozygous PDAC cell lines with single (C93A, C99A) and double (C93A + C99A) Ref-1 point mutations. This enabled detailed analysis of the individual and combined roles of Cys93 and Cys99 in Ref-1 redox signaling and their impact on various cancer phenotypes.</p><p><strong>Results: </strong>A single mutation at Cys93 decreased TF activation and reduced tumor cell survival <i>in vitro</i> and <i>in vivo</i>. These effects were similar but less pronounced in cells expressing C99A. The C93A + C99A double mutant further impaired redox signaling and decreased tumor growth and metastasis in orthotopic PDAC mouse models. All of these perturbations specifically disrupted Ref-1's redox activity without impacting its DNA repair function. Due to reduced levels of Ref-1 protein in the C93A + C99A tumor cells, add-back experiments with wild-type Ref-1 and C93A + C99A-Ref-1 examined the impact on cell survival and activation of TFs downstream of Ref-1. Transcriptomic analysis revealed distinct changes in redox and metabolic pathways, although these were less pronounced than those observed with the previously studied C65A mutant.</p><p><strong>Innovation and conclusion: </strong>These findings demonstrate contributory and cooperative, although secondary, roles for Cys93 and Cys99 in Ref-1 redox activity, establish new genetically engineered PDAC models, and underscore the therapeutic potential of targeting Ref-1 redox function in PDAC. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"15230864261489484"},"PeriodicalIF":6.8,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxic Preconditioning Prevents the Neonatal Lung Against Hyperoxia-Induced Ferroptosis Through the Nrf2-CBS Axis.","authors":"Salvador Pérez, Iván Millan, Elena Cubells, Sergio Rius-Pérez, Laura Torrejon, Jaime Ferrer, José M García-Verdugo, Máximo Vento, Isabel Torres-Cuevas","doi":"10.1177/15230864261486899","DOIUrl":"https://doi.org/10.1177/15230864261486899","url":null,"abstract":"<p><strong>Aims: </strong>Hyperoxia-induced oxidative injury contributes to ferroptosis and abnormal lung remodeling in preterm infants receiving oxygen therapy. We previously demonstrated that postnatal hypoxic preconditioning (HP) reduces hyperoxia-induced lung injury in a neonatal mouse model. In the present study, we investigated whether HP protects the neonatal lung against ferroptosis through a nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent mechanism involving transsulfuration and glutathione (GSH) metabolism.</p><p><strong>Results: </strong>In a neonatal mouse model, exposure to HP (FiO₂ = 0.14) prior to hyperoxic challenge (FiO₂ = 1.0) markedly reduced lipid peroxidation, pulmonary ferrous iron accumulation, ferroptosis-associated lipid remodeling, inflammation, and early fibrotic changes in the lung. Mechanistically, HP enhanced antioxidant defenses by increasing Nrf2 activity and promoting transsulfuration-dependent GSH synthesis through upregulation of cystathionine β-synthase (CBS) and xCT, leading to preservation of GSH homeostasis. To determine the functional role of Nrf2, Nrf2 knockout mice were subjected to the same HP/hyperoxia protocol. Nrf2 deficiency abolished the protective effects induced by HP, resulting in increased pulmonary ferrous iron levels, depletion of downstream transsulfuration metabolites and GSH, increased lipid peroxidation, reduced CBS and GPX4 expression, and persistent induction of fibrosis-associated genes.</p><p><strong>Innovation: </strong>This study demonstrates that postnatal HP protects the neonatal lung against hyperoxia-induced ferroptosis through an Nrf2-dependent transsulfuration program. Our findings identify the Nrf2-CBS axis as a key regulator of GSH homeostasis, ferroptosis resistance, and fibrotic remodeling in the developing lung.</p><p><strong>Conclusion: </strong>HP effectively attenuates hyperoxia-induced oxidative stress, ferroptosis, and profibrotic remodeling in neonatal lungs by preserving Nrf2-dependent GSH metabolism and redox homeostasis. These findings support HP as a promising therapeutic strategy to mitigate oxygen-induced pulmonary injury in preterm infants. <i>Antioxid. Redox Signal.</i> 00, 000-000.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"15230864261486899"},"PeriodicalIF":6.8,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}