Redox Biology最新文献

{"title":"Multi-organ toxicity via oxidative stress and disrupting mitochondrial plasticity induced by bendiocarb in zebrafish","authors":"Kyu Seomoon ,&nbsp;Hojun Lee ,&nbsp;Taeyeon Hong ,&nbsp;Junho Park ,&nbsp;Wei Ying ,&nbsp;Gwonhwa Song ,&nbsp;Wooyoung Jeong ,&nbsp;Whasun Lim","doi":"10.1016/j.redox.2025.104001","DOIUrl":"10.1016/j.redox.2025.104001","url":null,"abstract":"<div><div>Bendiocarb, a carbamate insecticide, is widely applied in various circumstances; however, it poses a potential threat to various non-target organisms. Although many researchers have focused on defining the toxic effects of bendiocarb, those associated with early and organ development remain poorly understood. In this study, we evaluated the developmental and organ-specific toxic mechanisms of bendiocarb in a zebrafish model. Exposure of bendiocarb decreased viability of zebrafish larvae by changing morphology and inducing production of reactive oxygen species with a decrease of the expression of antioxidant genes <em>cat</em> and <em>sod2</em>. In addition, bendiocarb affected mitochondrial bioenergetics and plasticity with reduction of mitochondrial complexes I, III, and V related genes leading to suppression of ATP generation. To investigate multi-organ toxic effects of bendiocarb, various transgenic zebrafish were utilized, for example, cardiac toxicity, impaired vasculature, and interfered blood flow were confirmed using <em>cmlc2:dsRed</em>, <em>fli1a:EGFP</em>, and <em>gata1a:dsRed</em>. Hepatotoxicity was examined using the <em>fabp10a:dsRed</em> model, and pancreatic toxicity was elucidated using the <em>elastase:EGFP</em> and <em>insulin:EGFP</em> models. Additionally, abnormal neuronal development was observed following treatment with <em>olig2:dsRed</em> and <em>gad1b:EGFP</em>. Moreover, changes at the molecular level by whole mount <em>in situ</em> hybridization and qPCR analyses were consistent with our observations. Furthermore, N-acetylcysteine (NAC) co-treatment substantially ameliorated developmental toxicity across multiple organ systems, including the cardiovascular, metabolic, and nervous systems. Taken together, this study provides novel perspectives on the system-level toxicity of bendiocarb and its molecular mechanisms of action in zebrafish.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 104001"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145894352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction notice to “Extracellular vesicle-mediated delivery of mitochondrial circRNA MTCO2 protects against cerebral ischemia by modulating mPTP-dependent ferroptosis” [Redox Biology 86 (2025) 103806]","authors":"Jialei Yang ,&nbsp;Shipo Wu ,&nbsp;Miao He","doi":"10.1016/j.redox.2025.103959","DOIUrl":"10.1016/j.redox.2025.103959","url":null,"abstract":"","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 103959"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145782735","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":"Celastrol nanomedicine eye drops restore redox homeostasis and prevents keratoconus progression via PI3K/AKT/AP-1 signaling","authors":"Ruixing Liu,&nbsp;Ruojun Ma,&nbsp;Nan Zhang,&nbsp;Xingchen Geng,&nbsp;Jingguo Li,&nbsp;Lei Zhu,&nbsp;Zhanrong Li","doi":"10.1016/j.redox.2025.103990","DOIUrl":"10.1016/j.redox.2025.103990","url":null,"abstract":"<div><div>Keratoconus (KC) is a progressive corneal disorder primarily driven by oxidative stress, though its precise molecular mechanisms remain incompletely understood, and effective pharmacological treatments are currently lacking. Our proteomic analysis of human KC tissues identified significant oxidative stress signatures and potential PI3K pathway in disease pathogenesis. Subsequent immunohistochemical and Western blot analyses confirmed a pronounced Nox/Nrf-2 redox imbalance - characterized by elevated Nox-4 and Nox-2 and suppressed Nrf-2 - along with activation of the PI3K/AKT/AP-1 signaling axis in KC corneas compared to normal corneas. To model KC-associated oxidative damage <em>in vitro</em>, hydrogen peroxide was used to stimulate rabbit corneal stromal cells. We developed cationic polymeric nanomicelles loaded celastrol (CPNM) to enhance corneal permeability and achieve sustain drug release. In a rabbit KC model, CPNM treatment attenuated corneal curvature progression, increased stromal thickness, and reduced reactive oxygen species (ROS) levels, as assessed by slit-lamp examination, histology, pachymetry, curvature measurements, and biochemical assays. Immunohistochemistry and immunofluorescence further demonstrated that CPNM downregulated PI3K/AKT/AP-1 pathway and restored Nox/Nrf-2 balance in corneal tissues. <em>In vitro,</em> CPNM suppressed ROS, rebalanced the Nox/Nrf-2 system, inhibited PI3K/AKT/AP-1 activation, and reduced matrix metalloproteinase activity. Our findings indicate that CPNM prevents KC progression by concurrently inhibiting oxidative stress <em>via</em> Nox/Nrf-2 balance and suppressing extracellular matrix degradation <em>via</em> PI3K/AKT/AP-1 signaling axis, positioning it as a promising clinical treatment strategy to halt KC progression.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 103990"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145822965","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":"Structural and functional modulation of human kynurenine aminotransferase I enhances selenium-driven redox metabolism for cancer therapy","authors":"Arun Kumar Selvam ,&nbsp;Renhua Sun ,&nbsp;Tatiana Sandalova ,&nbsp;Hugh Salter ,&nbsp;Adnane Achour ,&nbsp;Mikael Björnstedt","doi":"10.1016/j.redox.2025.103967","DOIUrl":"10.1016/j.redox.2025.103967","url":null,"abstract":"<div><div>Se-methylselenocysteine (MSC) is a redox-active selenium-containing amino acid with notable anticancer potential, requiring enzymatic activation for cytotoxicity. Human kynurenine aminotransferase 1 (hKYAT1) catalyzes MSC through transamination and β-elimination pathways, generating β-methylselenopyruvate and methylselenol, both of which induce oxidative stress and epigenetic modulation. To enhance MSC metabolism and its therapeutic efficacy, we performed site-directed mutagenesis targeting three critical hKYAT1 residues: Tyr101, Asp126, and Phe278. These mutants, along with wild-type hKYAT1, were expressed in hepatocellular carcinoma cell lines HepG2 and Huh7, and their impact on enzymatic activity, cytotoxic effects, apoptosis and chromatin remodeling were evaluated. Several mutations significantly enhanced MSC metabolism, with Y101H and F278A increasing both transamination and β-elimination activity, and D126L favoring β-elimination. These modifications led to a five-to 30-fold increase in MSC-induced cytotoxicity compared to wild-type hKYAT1. Additionally, mutant hKYAT1 expression altered histone deacetylase (HDAC) profiles, increased histone H4 acetylation, and activated apoptotic signaling through caspase cleavage and cytochrome <em>c</em> release. Collectively, our findings demonstrate that rational engineering of hKYAT1 can potentiate MSC metabolism and amplify its anticancer effects, offering a promising enzyme-targeting strategy for selenium-based cancer therapies.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 103967"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731553","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":"Persulfidation alters gene regulatory programs and promotes endothelial specification","authors":"Janina Wittig ,&nbsp;Ran Xu ,&nbsp;Fredy Delgado Lagos ,&nbsp;Maria-Kyriaki Drekolia ,&nbsp;Boran Zhang ,&nbsp;Ioannis Theodorou ,&nbsp;Yunyun Chen ,&nbsp;Yali Du ,&nbsp;Lavanya Gupta ,&nbsp;Cui Hanyu ,&nbsp;Li Yuanyuan ,&nbsp;Cheng Bo ,&nbsp;Stefan Günther ,&nbsp;Ilka Wittig ,&nbsp;Roxana Ola ,&nbsp;Jiong Hu ,&nbsp;Sofia-Iris Bibli","doi":"10.1016/j.redox.2025.103926","DOIUrl":"10.1016/j.redox.2025.103926","url":null,"abstract":"<div><div>Endogenously generated sulfides are conserved among species and tissues and exert multiple effects through diverse mechanisms. Although sulfides have been linked to cell fates, their role in pluripotent stem cell commitment remains unknown. Here we discovered that during directed differentiation of induced pluripotent stem cells, endogenous sulfide levels drop in all three germ layers, with the mesodermal lineage exhibiting the lowest capacity to generate these species at early specification events. Addition of a rapid releasing sulfide donor in iPSCs or mesodermal cells did not affect the redox surveillance mechanisms, however, it altered persulfidation and transcription of cell fate commitment pathways. In particular, sulfide supplementation in pluripotent stem cells reduced cell differentiation processes by preserving the activity of the stem cell transcription factors OCT4. In contrast, supplementation of sulfide during mesodermal lineage specification promoted persulfidation and activated the WNT signaling as well as enriched the activity of the ETS transcription factor family, resulting in increased transcription of angiogenic and vessel morphogenesis genes. Sulfide addition during the development of vascular organoids enhanced blood vessel morphogenesis. Taken together, these data position protein persulfidation as a timing-dependent regulator that preserves pluripotency prior to commitment but subsequently biases mesoderm toward endothelial specification, thereby emerging as a tractable redox modification for engineering stem cell fate and vascularization.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 103926"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145611801","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":"YAP/TEAD-activated TAG synthesis and peroxidation in lipid droplets confer ROS resistance in cancer stem cells","authors":"Jiun-Han Lin ,&nbsp;Tien-Wei Hsu ,&nbsp;Wei-Chung Cheng ,&nbsp;Chen-Chi Liu ,&nbsp;Anna Fen-Yau Li ,&nbsp;Mien-Chie Hung ,&nbsp;Han-Shui Hsu ,&nbsp;Shih-Chieh Hung","doi":"10.1016/j.redox.2025.103968","DOIUrl":"10.1016/j.redox.2025.103968","url":null,"abstract":"<div><h3>Background</h3><div>Cancer stem cells (CSCs) exhibit reduced levels of reactive oxygen species (ROS) despite increased oxidative phosphorylation, through mechanisms that remain poorly understood. Understanding these mechanisms could lead to new strategies for identifying and eradicating CSCs.</div></div><div><h3>Methods</h3><div>We combined lipidomic profiling, RNA-sequencing (RNA-seq), and TAGsig analysis to identify key lipids and genes involved in CSC-mediated resistance to ROS. These findings were further validated through a series of <em>in vitro</em> and <em>in vivo</em> experiments.</div></div><div><h3>Results</h3><div>We show that triacylglycerol (TAG), the main lipid in lung CSCs, localizes to peri-mitochondrial lipid droplets (LDs) and acts as a ROS scavenger. TAG undergoes peroxidation in these droplets upon exposure to H₂O₂, tBH, hypoxia, and FeCl₂, whereas in non-CSCs, oxidation occurs in mitochondria. RNA-seq analysis revealed upregulation of TAG synthesis enzymes (ACSL1/4, LPIN2, DGAT1/2, PNPLA3) in CSCs compared to non-CSCs. Inhibition and knockdown of DGAT1/2, which block TAG synthesis, led to reduced LDs and diminished sphere formation, radioresistance, and tumor initiation <em>in vivo</em>. Additionally, a six-gene TAG synthesis signature effectively predicted prognosis and survival in lung cancer patients. CSCs upregulated the ^Y357YAP/TEAD pathway to activate transcription of TAG synthesis genes, enhancing resistance to ROS.</div></div><div><h3>Conclusion</h3><div>We demonstrate that TAG in peri-mitochondrial LDs functions as a ROS scavenger, enabling CSCs to survive in hyperoxidative environments. Targeting the signaling pathways involved in TAG synthesis presents a potential strategy for eradicating CSCs.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 103968"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Porcine epidemic diarrhea virus promotes viral replication via ROS/HIF-1α-mediated glycolysis","authors":"Yafang Xu ,&nbsp;Jinqiu Zhang ,&nbsp;Chengwei Yin ,&nbsp;Laizhen Liu ,&nbsp;Zhenglei Wang ,&nbsp;Shaodong Fu ,&nbsp;Rong Fan ,&nbsp;Yanyan Zhao ,&nbsp;Jinfeng Miao","doi":"10.1016/j.redox.2026.104008","DOIUrl":"10.1016/j.redox.2026.104008","url":null,"abstract":"<div><div>Porcine epidemic diarrhea virus (PEDV), a highly pathogenic coronavirus, causes recurrent outbreaks of severe enteric disease, posing a significant threat to the global swine industry. The persistent challenge highlights the urgent need for a deeper understanding of host-virus interactions to improve prevention and control strategies. Here, we demonstrated that PEDV infection reprogrammed host metabolism toward aerobic glycolysis, a metabolic shift that not only facilitated viral replication but also established an immunosuppressive microenvironment. PEDV infection activated the hypoxia-inducible factor-1α (HIF-1α) pathway and induced mitochondrial dysfunction, leading to the accumulation of mitochondrial reactive oxygen species (mROS), which in turn stabilized HIF-1α, creating a positive feedback loop that amplified glycolytic gene expression and lactate production. We confirmed that glycolysis was essential for PEDV replication, and that elevated glucose levels enhanced replication efficiency. Furthermore, PEDV-induced glycolysis and lactate accumulation inhibited the generation of interferons (IFNs), thereby facilitating immune evasion. Collectively, our findings revealed a metabolic-immune axis exploited by PEDV to optimize viral replication and subvert host defenses. This study not only provides novel insights into the metabolic adaptations underlying PEDV pathogenesis but also highlights host metabolic pathways as potential therapeutic targets to combat PEDV and other related coronaviruses.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 104008"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NoxO1 promotes endosome formation and reduces intracellular vesicle processing","authors":"Maureen Hebchen ,&nbsp;Falk Herwig ,&nbsp;Tim Schader ,&nbsp;Manuela Spaeth ,&nbsp;Niklas Müller ,&nbsp;Katrin Schröder","doi":"10.1016/j.redox.2025.103973","DOIUrl":"10.1016/j.redox.2025.103973","url":null,"abstract":"<div><div>NADPH oxidase organizer 1 (NoxO1) is known as a scaffold cytoplasmic subunit of the reactive oxygen species (ROS) forming Nox1 complex. We previously identified an interaction between NoxO1 and Erbin, a cytosolic scaffold protein that associates with Epidermal Growth Factor Receptor (EGFR), but its ROS-independent roles remain poorly understood.</div><div>Here, we demonstrate that NoxO1 overexpression remodels the endolysosomal system by expanding early endosomes and lysosomes. A calibrated six-compartment ordinary differential equation model of EGFR trafficking predicts a slowed down intracellular trafficking: NoxO1 overexpression increased internalization rates by 14 % while reducing degradative sorting by 48 %, lysosomal transfer by 24 %, and final degradation by 41 %. Using fluorescent cargo (EGF and BSA), we confirmed enhanced internalization and cargo accumulation in lysosomes, supporting the idea of prolonged lysosomal retention in NoxO1 overexpressing cells. Mechanistically, NoxO1 activated transcription factor EB (TFEB), the master regulator of lysosomal biogenesis, in an Erbin-dependent but ROS independent manner. Proximity ligation assays revealed spatial association of NoxO1, Erbin, EGFR, and TFEB, suggesting a multi-protein regulatory complex. Genetic ablation of Erbin abolished NoxO1-induced increases in early endosome (EEA1) and lysosome (LAMP1) markers, confirming Erbin's essential role.</div><div>In conclusion, via its interaction with Erbin NoxO1 promotes activation of TFEB, contributes to lysosome formation while delaying cargo degradation.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 103973"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731680","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":"Combination of YAP inhibition and photodynamic therapy induces dual DNA damage and activates STING pathway to enhance immunotherapy in uveal melanoma","authors":"Shuyang Zhang ,&nbsp;Meijiao Song ,&nbsp;Jialu Zhang ,&nbsp;Jianshu Bai ,&nbsp;Xinyu Cao ,&nbsp;Lei Zhu ,&nbsp;Rui Tian","doi":"10.1016/j.redox.2025.103965","DOIUrl":"10.1016/j.redox.2025.103965","url":null,"abstract":"<div><div>Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and is highly aggressive, with no therapies shown to improve overall survival. Although immunotherapy achieves response rates of 33–40 % in advanced cutaneous melanoma, its efficacy in UM is disappointingly low, with only 3.6 % of patients responding. Herein, we report a nanomedicine-based strategy to enhance immunotherapy efficacy in UM by strong activation of the cyclic guanosine 3′,5′-cyclic monophosphate–adenosine monophosphate synthase (cGAS)–stimulator of interferon genes (STING) pathway through dual deoxyribonucleic acid (DNA) damage induced by Yes-associated protein (YAP) inhibition and photodynamic therapy (PDT). This approach, using hyaluronic acid nanoparticle (HANP)-formulated verteporfin (HANP/VP), concurrently induced nuclear- and mitochondrial-DNA damage, promoted immunogenic cell death (ICD), and drove T-lymphocyte infiltration into the tumor microenvironment (TME). When combined with anti–programmed death-ligand 1 (anti–PD-L1) antibody (Ab) and laser radiation (690 nm, 200 mW/cm², 10 min), HANP/VP significantly increased production of the pro-inflammatory cytokines interferon-γ (IFN-γ), IFN-β1, and tumor necrosis factor-α (TNF-α), enhanced dendritic-cell (DC) maturation and Cluster of Differentiation 8–positive (CD8⁺) T-cell expansion, suppressed tumor growth by 96.20 ± 7.22 %, and extended survival from 33 to &gt;80 days in orthotopic UM models. Importantly, rechallenge experiments confirmed durable antitumor immunity and prevention of UM recurrence. Overall, our findings established HANP/VP as a multifunctional nanomedicine that reprogrammed the TME and elicited potent antitumor immunity through dual DNA damage and STING activation. The study highlights a promising translational strategy for overcoming immunotherapeutic resistance in UM and converting immunologically “cold” tumors into “hot” ones, thereby improving responses to immune checkpoint blockade (ICB).</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 103965"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145689368","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":"Redox-dependent protein S-glutathionylation governs azacitidine sensitivity and resistance in AML","authors":"Dušan Nemes ,&nbsp;Michaela Myšáková ,&nbsp;Lubomír Minařík ,&nbsp;Anna Jonášová ,&nbsp;Tomáš Stopka ,&nbsp;Kristýna Gloc Pimková","doi":"10.1016/j.redox.2025.103958","DOIUrl":"10.1016/j.redox.2025.103958","url":null,"abstract":"<div><div>Disruption of redox metabolism is a hallmark of drug-resistant cancer cells, representing a major obstacle to the effective treatment of acute myeloid leukemia (AML). While recent studies have highlighted the importance of redox balance in AML therapy, the specific contribution of protein redox signaling to resistance remains poorly understood. Defining these mechanisms could uncover therapeutic vulnerabilities of resistant AML cells and guide the development of novel combination strategies. Here, we performed comprehensive mass spectrometry–based redox and quantitative proteomic profiling of AML cell lines and patient samples sensitive or resistant to the hypomethylating agent azacitidine (AZA). We demonstrate that AZA disrupts redox homeostasis, which inactivates the glyoxalase system and DNA damage response, and thereby induces cell death. In contrast, AZA resistance is associated with a redox reset characterized by elevated glutathione levels and diminished protein S-glutathionylation. Importantly, AZA failed to induce oxidation of proteins in these pathways in resistant cells and patient-derived AML samples. Pharmacological inhibition of glutathione synthesis restored protein S-glutathionylation and resensitized resistant AML cells to AZA.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"89 ","pages":"Article 103958"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145689935","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}