Redox Biology最新文献

{"title":"DMNQ induces ferroptosis and augments the efficacy of anti-PD-L1 immunotherapy in gastric cancer via the STAT3/SLC1A4 axis to mediate cysteine metabolism reprogramming","authors":"Wenshuai Zhu ,&nbsp;He Qi ,&nbsp;Fubo Jing ,&nbsp;Yuxuan Shi ,&nbsp;Yuanxin Xing ,&nbsp;Xiaoli Ma ,&nbsp;Bin Ning ,&nbsp;Yunshan Wang ,&nbsp;Yanfei Jia","doi":"10.1016/j.redox.2026.104055","DOIUrl":"10.1016/j.redox.2026.104055","url":null,"abstract":"<div><div>Ferroptosis plays an essential role in tumor progression. Therapeutic agents targeting ferroptosis emerge as a novel strategy for cancer treatment. Abnormal amino acid metabolism can control ferroptosis sensitivity in cancer cells, and lead to the deficiency or accumulation of specific products in the tumor microenvironment (TME). Here, we demonstrated that 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) induced growth inhibition in gastric cancer cell lines, primary gastric cancer mouse models, and patient-derived tumor organoids. DMNQ exerted ferroptosis inducing effects by inhibiting STAT3 phosphorylation and transcriptional activity. Importantly, the STAT3/SLC1A4 axis regulated cysteine uptake, tumor killing by T cells and the efficacy of anti-PD-L1 immunotherapy. Collectively, our findings revealed a critical mechanism by which DMNQ exerts a significant anti-cancer role in gastric cancer through increasing ferroptosis to enhance cancer immunotherapy and may provide a novel therapeutic strategy for gastric cancer.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104055"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048384","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":"Lactate-driven ATP6V1B2 lactylation triggers asthmatic inflammation by linking lysosomal dysfunction to mitochondrial ROS-dependent pyroptosis","authors":"Qiaoyun Bai ,&nbsp;Ningpo Ding ,&nbsp;Rixin Feng ,&nbsp;Fengxiang Shang ,&nbsp;Zongqi Wang ,&nbsp;Liangchang Li ,&nbsp;Zhiguang Wang ,&nbsp;Yihua Piao ,&nbsp;Guangyu Jin ,&nbsp;Yilan Song ,&nbsp;Guanghai Yan","doi":"10.1016/j.redox.2026.104059","DOIUrl":"10.1016/j.redox.2026.104059","url":null,"abstract":"<div><div>Immunometabolic reprogramming is increasingly recognized as a driver of asthma pathogenesis, yet the molecular mechanisms linking lactate accumulation to airway inflammation via protein lactylation (Kla) remain elusive. In this study, we integrated a house dust mite (HDM)-induced asthma model with quantitative lactylomics to identify ATP6V1B2, a key V-ATPase subunit, as a core lactylation target. Combined molecular dynamics simulations and biochemical analyses revealed that intracellular <span>l</span>-lactate triggers lactylation at K108/K109. This modification restricts ATP6V1B2 conformational flexibility, leading to the disassembly of the V1–V0 complex and subsequent loss of proton pump activity. Crucially, the lactylation event was validated in primary human bronchial epithelial cells (HBEs), confirming that HDM and <span>l</span>-lactate stimulation induce ATP6V1B2 lactylation, thereby ensuring the clinical relevance of our findings. We demonstrate that this loss-of-function precipitates lysosomal alkalinization and membrane permeabilization (LMP). Crucially, LMP acts as a central node that bifurcates into two pathogenic cascades: it triggers a catastrophic mitochondrial ROS burst via Cathepsin B leakage. This oxidative burst functions as a pivotal redox signal that initiates a non-canonical Caspase-8/3/GSDME-dependent pyroptosis pathway, distinct from intrinsic apoptosis. In vivo, blocking ATP6V1B2 lactylation using an AAV-delivered lactylation-deficient (2 KR) mutant successfully severed this metabolic-inflammatory loop, significantly attenuating airway inflammation, Th2 cytokine release, and tissue pyroptosis. These findings characterize a novel \"<span>l</span>-lactate–ATP6V1B2–GSDME\" axis, establishing ATP6V1B2 lactylation as a critical metabolic switch connecting lysosomal damage to inflammatory cell death, thereby identifying a potential therapeutic target for metabolic dysregulation in chronic asthma with severe pathology.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104059"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089392","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":"Ferrostatin-1 protects against early sepsis-induced acute lung injury by suppressing lipid peroxidation–driven NINJ1-mediated DAMP release and neutrophil activation","authors":"Fang Xiao ,&nbsp;Donghua Li ,&nbsp;Miao Yu ,&nbsp;Yunfeng Zhu ,&nbsp;Guorong Huang ,&nbsp;Zhilei Huang ,&nbsp;Yufang Wang ,&nbsp;Jialin Li ,&nbsp;Dongmei Zhong ,&nbsp;Huan Ma ,&nbsp;Kunyu Liao ,&nbsp;Yongshan Liu ,&nbsp;Yalin Zhang ,&nbsp;Xiangdong Guan ,&nbsp;Changjie Cai ,&nbsp;Jing Tang ,&nbsp;Tianqin Peng ,&nbsp;Fu-Li Xiang ,&nbsp;Jie Xu","doi":"10.1016/j.redox.2026.104004","DOIUrl":"10.1016/j.redox.2026.104004","url":null,"abstract":"<div><div>Sepsis-induced acute lung injury (ALI) is a critical condition driven by neutrophil-dominated inflammation, lytic cell death and the subsequent DAMP release, etc. We tested whether the radical-trapping antioxidant Ferrostatin-1 (Fer-1) interrupts lipid peroxidation induced DAMP release and limits early lung injury in sepsis. We found that Fer-1 improved survival, preserved alveolar architecture, reduced lung-injury scores, and suppressed pulmonary inflammatory cytokine expression in a murine cecal ligation and puncture (CLP) model. Lung tissue RNA-sequencing showed that Fer-1 attenuated the CLP-induced inflammatory and chemotaxis transcriptome and significantly reduced neutrophil infiltration. <em>In vitro</em>, Fer-1 protected cells from lipid peroxidation–induced lytic death and impaired the release of large DAMPs associated with NINJ1 pathway, indicated Fer-1 acts upstream of NINJ1 to preserve membrane integrity. Fer-1 also directly lowered lipid peroxidation and reduced lipopolysaccharide (LPS)–induced IL-1β and IL-6 transcription and secretion in neutrophils, an effect reversed by pharmacological JNK/p38 activation. Together, our results indicate that Fer-1 functions as a dual-action modulator that prevents DAMP release and blunts neutrophil-driven inflammation escalation, thereby interrupting the lipid peroxidation–NINJ1–DAMP release axis, and mitigating early septic ALI.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104004"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902651","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":"LRRK2 controls COX assembly through regulation of redox status of mitochondrial copper chaperones","authors":"Tae Young Kim ,&nbsp;Eun-Hae Jang ,&nbsp;Yun-Hee Bae ,&nbsp;Eun-Mi Hur ,&nbsp;Byoung Dae Lee","doi":"10.1016/j.redox.2026.104061","DOIUrl":"10.1016/j.redox.2026.104061","url":null,"abstract":"<div><div>Mitochondrial dysfunction is a common pathological hallmark of neurodegenerative diseases. In Parkinson's disease (PD), the most popular age-related movement disorder, the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) is closely associated with mitochondrial energetic deficits, reflecting their exceptionally high metabolic demand. The electron transport chain (ETC), essential for ATP production, comprises multiple protein complexes that require coordinated assembly and redox-sensitive regulation. In this study, we identified LRRK2—the most common genetic contributor to both familial and sporadic PD—as a regulator of cytochrome <em>c</em> oxidase (COX), the terminal enzyme of the ETC, through its control of the redox status of mitochondrial copper chaperones. Expression of pathogenic LRRK2 G2019S mutant increased the proportion of reduced (Cu-deficient) forms of COX11 and SCO1, two chaperones essential for COX metalation, thereby impairing COX assembly and promoting ETC dysfunction. Within this regulatory hierarchy, COX19 functions as a downstream effector of LRRK2 and an upstream modulator of COX11 and SCO1 redox status. Moreover, LRRK2 and COX19 reciprocally regulate each other's expression and cooperatively disrupted COX biogenesis. <em>In vivo</em>, exogenous expression of COX19 via AAV gene delivery induced dopaminergic neurodegeneration and motor deficits, which were effectively rescued by pharmacological inhibition of LRRK2 kinase activity. Together, these findings define a positive feedback LRRK2–COX19 signaling axis that governs mitochondrial redox homeostasis and COX assembly, highlighting a promising therapeutic target for PD and related mitochondrial disorders.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104061"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146071599","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":"Epithelial redox stress programs macrophage immunometabolism through a ZNF24-MIF–NF–κB pathway in chronic nonbacterial prostatitis","authors":"Fei Zhang ,&nbsp;Andong Zhang ,&nbsp;Tong Meng ,&nbsp;Xianhong Liu,&nbsp;Cheng Yang,&nbsp;Chaozhao Liang,&nbsp;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":"2026-03-01","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}

{"title":"Molecular determinants of allosteric modulation of protein disulfide isomerase by small-molecule b′-ligands","authors":"Nathan Ponzar ,&nbsp;Anna Pagotto ,&nbsp;Srija Bandyopadhayay ,&nbsp;Marvin J. Meyers ,&nbsp;Vincenzo De Filippis ,&nbsp;Robert Flaumenhaft ,&nbsp;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":"2026-03-01","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}

{"title":"Female sex is a risk factor for exacerbated lipid peroxidation and disease in murine retinitis pigmentosa","authors":"Katri Vainionpää,&nbsp;Anna Kalatanova,&nbsp;Umair Seemab,&nbsp;Ahmed B. Montaser,&nbsp;Henri Leinonen","doi":"10.1016/j.redox.2025.103987","DOIUrl":"10.1016/j.redox.2025.103987","url":null,"abstract":"<div><div>Oxidative stress is an important aspect in retinal degenerations that could be targeted in various forms of currently untreatable diseases. It is generally believed that males are more predisposed to oxidative stress than females due to their higher metabolic activity and/or lower antioxidant capacity. However, studies using mouse disease models have demonstrated that photoreceptor degeneration progresses faster in females. Sex hormones likely play a role, but the cellular mechanism behind the sex difference is unclear. In the current study, we confirmed that the accelerated disease phenotype in female rd10 and P23H retinitis pigmentosa mice coincides with sexual maturity, and further, we found that it co-occurs with increased retinal lipid peroxidation. Instead, protein oxidation and inflammatory marker levels were similar between the sexes. Retinal lipid profiling revealed higher levels of polyunsaturated fatty acid (PUFA)-containing lipids in healthy 2-month-old female mice compared to males, whereas before puberty the sex difference in retinal PUFAs was absent. However, the association between elevated long-chain PUFAs in female C57BL/6J mouse retinas and the increased lipid peroxidation in female RP mice on the same background remains correlative rather than causal. Analysis of open bulk retina transcriptomic data from middle-aged humans found supplemental evidence of sex-related differences in retinal energy metabolism pathways. In addition to mechanistic studies aimed at uncovering the causes of differential lipid peroxidation between sexes, further research is needed to investigate sex differences in retinal metabolism and lipid composition across animal species. Our findings highlight the importance of considering sex differences when conducting preclinical experiments using RP models.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 103987"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145822966","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":"Prenylterphenyllin, a regulator of P53, inhibits colorectal cancer progression through oxidative stress and energy metabolism pathway","authors":"Yuhan Zhang ,&nbsp;Yueqing Han ,&nbsp;Songmao Li ,&nbsp;Ruimin Shan ,&nbsp;Ling Lin ,&nbsp;Zhengyu Gu ,&nbsp;Ruiyu wang ,&nbsp;Yun Chen ,&nbsp;Jiao Xiao ,&nbsp;Fangmei An ,&nbsp;Chupeng Hu ,&nbsp;Chunyan He","doi":"10.1016/j.redox.2025.103993","DOIUrl":"10.1016/j.redox.2025.103993","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is one of the most prevalent and deadly cancers globally, with poor prognosis primarily due to metastasis and resistance to conventional therapies. This study evaluated the antitumor potential of prenylterphenyllin, a natural product derived from <em>Aspergillus candidus</em>. Prenylterphenyllin significantly reduced CRC cells viability and migration, while promoting apoptosis and cell-cycle arrest. Transcriptomic analysis showed activation of the p53 signaling pathway and inhibition of cell-cycle-related genes. Prenylterphenyllin also disrupted mitochondrial function and oxidative phosphorylation, increasing oxidative stress. <em>In vivo</em>, it suppressed tumor growth and lung metastasis without notable toxicity. These results highlight that prenylterphenyllin is a promising candidate for CRC therapy, capable of inhibiting tumor growth, migration, and metastasis while inducing apoptosis through the modulation of energy metabolism and oxidative stress. As a promising candidate, prenylterphenyllin may offer new therapeutic opportunities for CRC, particularly for metastatic disease. Collectively, this study identifies prenylterphenyllin as a novel therapeutic candidate for CRC and illuminates its promising therapeutic potential.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 103993"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145915289","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":"Methylation reader MBD2-mediated GPX4 transcriptional repression drives ovarian granulosa cell ferroptosis in PCOS","authors":"Zhengquan Zhu ,&nbsp;Yihan Wang ,&nbsp;Xinye Yu ,&nbsp;Tingyu Wang ,&nbsp;Yin Li ,&nbsp;Ruizhe Wang ,&nbsp;Haiyun Chen ,&nbsp;Binjia Ruan ,&nbsp;Wangsen Cao ,&nbsp;Gaojian Tao ,&nbsp;Yong Wang ,&nbsp;Daojuan Wang","doi":"10.1016/j.redox.2026.104034","DOIUrl":"10.1016/j.redox.2026.104034","url":null,"abstract":"<div><div>Arrested follicular development and anovulation are hallmarks of polycystic ovary syndrome (PCOS), in which granulosa cell (GC) ferroptosis is emerging as a potential contributor. However, its precise role and regulation remain largely unknown. Here, we identify a methyl-CpG-binding domain protein 2 (MBD2)-driven ferroptotic program as a central pathogenic mechanism in PCOS. In a dehydroepiandrosterone (DHEA)-induced PCOS mouse model, GCs exhibited marked ferroptotic alterations and transcriptional suppression of glutathione peroxidase 4 (GPX4), a key anti-ferroptotic enzyme. GC-specific Gpx4 knockout exacerbated ferroptosis, impaired follicular maturation, reduced corpora lutea formation, and aggravated PCOS pathology. GPX4 repression was associated with increased DNA methyltransferases (DNMTs), elevated DNA Methyl-reading protein MBD2 and hypermethylation of the <em>Gpx4</em> promoter. Pharmacological inhibition of MBD2 with KCC-07, or DNMT blockade with 5-Azacytidine, restored GPX4 expression, reduced lipid peroxidation and GC ferroptosis, and alleviated ovarian dysfunction. Integrative ATAC-seq and RNA-seq analyses revealed enhanced <em>Gpx4</em> promoter accessibility in PCOS ovaries, where MBD2, MAZ, HDAC3 and NCoR assembled into a repressive complex that was interrupted by KCC-07 treatment. Importantly, pharmacologic GPX4 inhibition with RSL3 or GC-specific Gpx4 deletion abrogated the protective effects of MBD2 inhibition, establishing GPX4 repression as the critical downstream effector. Collectively, these findings uncover an MBD2-driven epigenetic program that silences GPX4, triggers GC ferroptosis, and promotes PCOS pathogenesis. Targeting MBD2 to restore epigenetic control of ferroptosis offers a promising therapeutic strategy for PCOS.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104034"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995159","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":"Intercellular mitochondrial transfer rewires redox signaling and metabolic plasticity: mechanisms, disease relevance and therapeutic frontiers","authors":"Jiahui Wang ,&nbsp;Rongqing Li ,&nbsp;Li Qian","doi":"10.1016/j.redox.2026.104019","DOIUrl":"10.1016/j.redox.2026.104019","url":null,"abstract":"<div><div>Intercellular mitochondrial transfer is recognized as a central mechanism that shapes redox homeostasis, metabolic plasticity, and cellular resilience across multiple tissues. Through tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junction channels (GJCs), and cell fusion, mitochondria move between donor and recipient cells to restore bioenergetic capacity, buffer oxidative stress, and tune redox-sensitive signaling networks. Recent work has begun to clarify the regulatory framework governing donor-recipient specificity, cargo selection, and the stress-activated cues that trigger organelle exchange. Mitochondrial transfer also exerts distinct, context-dependent influences on disease trajectories. It mitigates injury in neurological damage, ischemia-reperfusion conditions, immune dysfunction, aging, and inflammatory pain, largely by reprogramming mitochondrial function and reactive oxygen species (ROS) dynamics. Conversely, in cancer, mitochondrial acquisition enhances metabolic flexibility, invasiveness, and resistance to therapy. Current therapeutic approaches, including mitochondrial transplantation, EV-based delivery systems, and mitochondria-enhanced immune cells, highlight the translational potential of manipulating mitochondrial exchange, yet face challenges such as mitochondrial fragility, inefficient targeting, and immunogenicity. Deeper mechanistic insight into how mitochondrial transfer remodels redox signaling and metabolic adaptation will be essential for converting this biological process into next-generation organelle-level interventions for redox-driven disorders.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104019"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957337","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}