Redox Biology最新文献

{"title":"Development of a novel HDAC6 PET imaging agent uncovers associations between HDAC6 overexpression and neuroinflammation in depression","authors":"Yanting Zhou ,&nbsp;Yuheng Zou ,&nbsp;Xiao Zhong ,&nbsp;Hongyan Li ,&nbsp;Jingyi Yang ,&nbsp;Hui Meng ,&nbsp;Weiyao Xie ,&nbsp;Pan Yao ,&nbsp;Xiaoai Wu ,&nbsp;Huawei Cai ,&nbsp;Lin Li ,&nbsp;Changning Wang ,&nbsp;Wei Zhang ,&nbsp;Ping Bai","doi":"10.1016/j.redox.2026.104014","DOIUrl":"10.1016/j.redox.2026.104014","url":null,"abstract":"<div><div>Histone deacetylase 6 (HDAC6) represents a compelling target in major depressive disorder (MDD) pathophysiology, yet <em>in vivo</em> investigation has been constrained by inadequate imaging capabilities. Here, we report the development and validation of [¹⁸F]PB200, a novel positron emission tomography (PET) radiotracer specifically targeting brain HDAC6. PB200 was engineered with nanomolar affinity, high HDAC6 selectivity, and excellent blood-brain barrier permeability. [¹⁸F]PB200 was successfully synthesized in a radiochemical yield of 13 ± 4 % and validated through <em>in vitro</em> autoradiography and <em>in vivo</em> PET imaging across rodent and non-human primate models. We subsequently employed [¹⁸F]PB200 alongside TSPO-targeted [¹⁸F]FEPPA PET imaging in a chronic unpredictable mild stress (CUMS) mouse model of depression. This dual-tracer approach, complemented by <em>in vitro</em> experiments, revealed significant HDAC6 upregulation occurring concurrently with enhanced neuroinflammatory markers, including microglial activation and elevated pro-inflammatory cytokines. Our findings provide the first <em>in vivo</em> molecular imaging evidence directly linking HDAC6 upregulation to depressive pathophysiology and associated neuroinflammation. This work illuminates the molecular relationship between depression and neuroinflammation while establishing [¹⁸F]PB200 as a valuable tool for evaluating HDAC6-targeted therapeutic interventions, potentially advancing precision diagnosis and treatment approaches for depression.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104014"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957333","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":"RIPK3-driven phosphorylation of MFN2 orchestrates endoplasmic reticulum-mitochondria interaction and cardiomyocyte stress responses","authors":"Yu Wang ,&nbsp;Tao Xu ,&nbsp;Qi Li ,&nbsp;Lin Ye ,&nbsp;Peiyan Wang ,&nbsp;Puhan Wang ,&nbsp;Yihan Song ,&nbsp;Xiang Ao ,&nbsp;Jianxun Wang ,&nbsp;Wei Ding","doi":"10.1016/j.redox.2026.104006","DOIUrl":"10.1016/j.redox.2026.104006","url":null,"abstract":"<div><h3>Background</h3><div>Recent studies have demonstrated that necroptosis is one of the main forms of cardiomyocyte death in heart diseases. However, the crosstalk between the death-receptor necroptosis pathway and the mitochondrial necroptosis pathway remains largely unknown. It has been reported that Mitofusin 2 (MFN2) can promote myocardial injury by inducing Endoplasmic Reticulum (ER)-mitochondria interaction. The purpose of this study was to investigate whether MFN2 promotes cardiac necroptosis and myocardial ischemia/reperfusion (I/R) injury by regulating ER-mitochondrial interactions, and whether this function of MFN2 can be regulated by the death-receptor necroptosis pathway.</div></div><div><h3>Methods</h3><div>Myocardial necroptosis was induced by H₂O₂ in H9c2 cardiomyocytes in vitro and through left anterior descending (LAD) ligation and subsequent reperfusion in C57/BL6 mice in vivo. ER-mitochondria interaction was detected by immunofluorescence. Calcium levels were analyzed by Rhod-AM staining. The interaction between MFN2 and Receptor-interacting protein kinase 3 (RIPK3) was explored by co-immunoprecipitation and immunofluorescence. The phosphorylation site of MFN2 was examined and measured via mass spectrometry analysis. Additionally, a customized MFN2 phosphorylation-specific antibody was used to detect the role of the Threonine 130 site of MFN2 in myocardial necroptosis. In vivo, MFN2 cardiac-specific knockout mice were constructed to further explore the effect of MFN2 on myocardial I/R injury and necroptosis.</div></div><div><h3>Results</h3><div>Our results showed that MFN2 participated in H₂O₂-induced cardiomyocyte necroptosis by promoting the formation of ER-mitochondrial interactions and ER-mitochondrial Ca²⁺ transfer, which could be regulated by RIPK3 via phosphorylating MFN2 at the Threonine 130 site. Moreover, mitochondrial Ca²⁺ overload induced mPTP opening and subsequent activation of Calpain1, resulting in the inhibition of mitophagy initiation. Both of these pathways could promote cardiac necroptosis. Furthermore, our results revealed that cardiac-specific knockout of MFN2 could attenuate myocardial I/R injury.</div></div><div><h3>Conclusion</h3><div>Our findings reveal that RIPK3 can mediate MFN2 phosphorylation to promote ER-mitochondria interaction and mitochondrial Ca²⁺ overload, leading to the induction of cardiac necroptosis.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104006"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903372","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":"Tumor-intrinsic redox programming drives an SPP1-CD44 axis of immune suppression in uveal melanoma","authors":"Tongxin Ge ,&nbsp;Yun Yang ,&nbsp;Wenyue Zhang ,&nbsp;Mengyao Li ,&nbsp;Xiang Gu ,&nbsp;Ludi Yang ,&nbsp;Renbing Jia ,&nbsp;Xingyun Wang ,&nbsp;Xianqun Fan ,&nbsp;Ai Zhuang","doi":"10.1016/j.redox.2026.104011","DOIUrl":"10.1016/j.redox.2026.104011","url":null,"abstract":"<div><div>Uveal melanoma (UM) is a rare yet aggressive malignancy with a high propensity for distant metastasis and poor response to systemic therapies, including immunotherapies. Although recent single-cell studies have uncovered pronounced intratumoral heterogeneity and an immunosuppressive tumor microenvironment, the tumor-intrinsic metabolic programs that drive immune escape remain poorly defined. Here, we performed single-cell RNA sequencing on primary UM specimens to generate a high-resolution atlas of tumor and immune cell states. We identified a redox-optimized melanoma subpopulation under heavy metabolic-proteostatic demand, characterized by intensive protein secretory activity and elevated antioxidant defenses. This adaptive state is required to sustain the robust secretion of the matricellular protein SPP1, which suppressed the proliferation and function of CD8⁺ T cells through CD44 engagement. Disruption of redox equilibrium by enhancing reactive oxygen species (ROS) via a mitochondria-targeted oxidative phosphorylation inhibitor triggered endoplasmic reticulum stress and downregulated SPP1 expression, thereby defining a direct metabolic-immune regulatory axis. Together, our findings reveal a previously unrecognized ROS-SPP1-CD44 axis that links tumor redox homeostasis to immune evasion, providing mechanistic insight into the immune-resistant phenotype of UM and suggesting potential therapeutic vulnerabilities within the metabolic-immune crosstalk.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104011"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957371","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":"UFMylation deficiency in hepatocytes activates the KEAP1-NRF2 pathway and contributes to hepatocarcinogenesis","authors":"Qian Liang ,&nbsp;Shiwen Xu ,&nbsp;Yaoyao Fang ,&nbsp;Xue Wang ,&nbsp;Yang Xiao ,&nbsp;Yiwen Wang ,&nbsp;Shujuan Li ,&nbsp;Qifan Guo ,&nbsp;Yu Cao ,&nbsp;Ying Cao ,&nbsp;Chao Liu ,&nbsp;Yuqin Zhao ,&nbsp;Yan Luo ,&nbsp;Anqi Wu ,&nbsp;Miao Wang ,&nbsp;Junping Shi ,&nbsp;Guoqing Li ,&nbsp;Yu-Sheng Cong","doi":"10.1016/j.redox.2026.104046","DOIUrl":"10.1016/j.redox.2026.104046","url":null,"abstract":"<div><div>The Kelch-like ECH-associated protein 1 (KEAP1) - Nuclear factor erythroid 2-related factor 2 (NRF2) pathway plays a central role in maintaining cellular redox balance, aberrant activation of the KEAP1-NRF2 pathway is involved in a variety of human malignant tumors including hepatocellular carcinoma. However, the underlying mechanisms remain unclear. UFMylation is a type of ubiquitin-like modifications with important biological functions, its deficiency is implicated in several pathogenesis. In this study, we show that hepatocyte specific <em>Ufl1</em> knockout in mice results in several hepatic pathological alterations and promotes the development of diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Furthermore, we identified KEAP1 as an UFMylation substrate, and deficiency in UFMylation modification resulted in ubiquitin-mediated degradation of KEAP1, and subsequent nuclear accumulation of NRF2, and activation of the KEAP1-NRF2 pathway. Consistently, we found that UFL1 expression is decreased and positively correlated with the level of KEAP1 in liver cancer samples. Our results suggest that UFL1 plays an important role in liver pathophysiology, in part by regulating the KEAP1-NRF2 pathway, thus provides novel insights into the molecular basis of hepatocarcinogenesis.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104046"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048386","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":"Intergenerational and organ-specific alterations in mitochondrial DNA copy number following preconception irradiation","authors":"Ryosuke Seino ,&nbsp;Hisanori Fukunaga","doi":"10.1016/j.redox.2026.104054","DOIUrl":"10.1016/j.redox.2026.104054","url":null,"abstract":"<div><div>Ionizing radiation, a potent inducer of redox stress, perturbs both nuclear and mitochondrial genomes, yet how such stress shapes mitochondrial inheritance across generations remains unclear. In this study, we examined intergenerational and organ-specific mitochondrial responses to parental X-ray irradiation in mice. Eight-week-old male and female C57BL/6N mice were exposed to 2 Gy of single whole-body X-ray irradiation before mating, generating paternal-, maternal-, and dual-irradiated lineages. In the parents, peripheral blood-derived mitochondrial DNA copy number (mtDNAcn) transiently increased one day after exposure, consistent with a rapid mitochondrial response to redox stress. In newborn offspring, mtDNAcn displayed clear organ- and parent-of-origin specificity: brain mtDNAcn decreased in paternal- and dual-irradiation lineages, heart mtDNAcn remained unchanged, and liver mtDNAcn showed the most pronounced depletion across all irradiated lineages. No significant inter-organ correlations in mtDNAcn were observed. All irradiated lineages exhibited increased body weight and increased liver weight at birth, with a significant positive association between these traits. Liver weight was negatively associated with hepatic mtDNAcn. Multiple regression analysis further showed that maternal pre-exposure mtDNAcn and offspring hepatic mtDNAcn independently predicted neonatal liver weight. Taken together, these findings demonstrate that preconception irradiation induces acute mitochondrial responses in parents and is associated with intergenerational, organ-specific mtDNAcn dysregulation that manifests as offspring birth outcomes. Parental irradiation perturbs organ-specific mitochondrial genome regulation and predisposes the next generation to altered growth-related traits.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104054"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089391","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":"A LNK–CBL–HNRPA2B1–GPX4 signaling axis mediates dopaminergic neuron vulnerability to ferroptosis in Parkinson's disease","authors":"Ziqi Liu ,&nbsp;Ruoxun Wang ,&nbsp;Min Shen ,&nbsp;Xinrui Lan ,&nbsp;Weixing Yan ,&nbsp;Sainan Wang ,&nbsp;Mingfeng Jiang ,&nbsp;Rongqing Li ,&nbsp;Jie Zhao ,&nbsp;Qicheng Wang ,&nbsp;Xinyi Xv ,&nbsp;Jingwen Zhou ,&nbsp;Xin Pan ,&nbsp;Wei Li ,&nbsp;Weijuan Gong ,&nbsp;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":"2026-03-01","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}

{"title":"Patient-derived lung organoids from bronchoalveolar lavage capture epithelial heterogeneity and disease biology in bronchopulmonary dysplasia","authors":"Shilpa Sonti ,&nbsp;Abiud Cantu ,&nbsp;Manuel Cantu Guttierez ,&nbsp;Connor Leek ,&nbsp;Phinzy Pelton ,&nbsp;Erik A. Jensen ,&nbsp;Krithika Lingappan","doi":"10.1016/j.redox.2026.104057","DOIUrl":"10.1016/j.redox.2026.104057","url":null,"abstract":"<div><div>Modeling neonatal lung disease <em>ex vivo</em> to elucidate disease pathogenesis is particularly challenging. We hypothesized that airway organoids derived from bronchoalveolar lavage (BAL) samples obtained from intubated preterm infants with bronchopulmonary dysplasia (BPD) will recapitulate the epithelial heterogeneity seen in human airways and can be used to study lung injury and therapeutic responses. Here, we demonstrate that BAL sample-derived airway organoids from ventilator-dependent patients with established BPD exhibited cellular heterogeneity consistent with that observed in the human airway. Developed organoids contain basal cell progenitors and a spectrum of differentiated epithelial subtypes, including secretory, ciliated, PNECs, and hillock cells. Hyperoxia exposure and treatment with dexamethasone caused significant cellular transcriptional changes and highlighted biological pathways, both known and novel, with distinct findings based on sex as a biological variable. Findings were validated in an independent dataset from human BPD lung samples. Infant BAL-derived human lung organoids represent a cutting-edge model that bridges a critical gap in BPD research. They combine the advantages of being patient-specific and capturing developmental lung biology, with the experimental flexibility of an <em>in vitro</em> system.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104057"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146072061","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":"Zinc overload disrupts SoxR [2Fe–2S] clusters to drive redox-metallic crosstalk via SoxS-ZnuACB in Escherichia coli","authors":"Jie Feng,&nbsp;Feng Liang,&nbsp;Yongguang Zhou,&nbsp;Shihao Wen,&nbsp;Yue Chen,&nbsp;Binjie Ge,&nbsp;Wenjing Zhang,&nbsp;Jie Wang,&nbsp;Runyu Chen,&nbsp;Yin Zhang,&nbsp;Jianghui Li,&nbsp;Wu Wang,&nbsp;Guoqiang Tan","doi":"10.1016/j.redox.2026.104013","DOIUrl":"10.1016/j.redox.2026.104013","url":null,"abstract":"<div><div>Here, we demonstrate that excess zinc disrupts bacterial redox sensing by specifically disassembling the [2Fe–2S] cluster of SoxR – a master oxidative stress sensor in <em>Escherichia coli</em>. This impairment couples zinc overload to dysregulated oxidative defense, revealing a previously unrecognized metal-redox crosstalk mechanism. Using electron paramagnetic resonance (EPR) and UV–visible spectroscopy, we demonstrated that excess zinc specifically disrupts the assembly of the [2Fe–2S] cluster in redox-sensitive SoxR. Additionally, we assessed the expression levels of genes within this pathway using quantitative real-time PCR (qPCR) and quantified intracellular zinc and iron levels by inductively coupled plasma mass spectrometry (ICP-MS) to evaluate the roles of SoxS and the zinc uptake transporter ZnuACB in maintaining zinc homeostasis. Furthermore, we investigated the roles of SoxR, SoxS, and ZnuACB in bacterial zinc homeostasis through plate growth assays and gene knockout experiments. We establish that zinc excess disassembles SoxR [2Fe–2S] clusters as a molecular switch that dysregulates the SoxS-ZnuACB/SOD axis, converting zinc toxicity into oxidative vulnerability. This mechanistic insight exposes a bacterial Achilles' heel: targeting Fe–S cluster integrity disrupts redox-metal homeostasis, providing a strategy to combat antibiotic-resistant pathogens.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104013"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145929095","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":"Unravelling the anti-cancer mechanisms elicited by non-covalent thioredoxin reductase inhibitors for triple negative breast cancer therapy","authors":"Abigail Rullo ,&nbsp;Brenna Flowers ,&nbsp;Keacha Chang ,&nbsp;An Zhang ,&nbsp;Valentina Z. Petukhova ,&nbsp;Luke Harding ,&nbsp;Sammy Y. Aboagye ,&nbsp;Maurizio Bocchetta ,&nbsp;Wei Qiu ,&nbsp;David L. Williams ,&nbsp;Francesco Angelucci ,&nbsp;Pavel A Petukhov ,&nbsp;Irida Kastrati","doi":"10.1016/j.redox.2025.103980","DOIUrl":"10.1016/j.redox.2025.103980","url":null,"abstract":"<div><div>Thioredoxin reductases (cytosolic TXNRD1 and mitochondrial TXNRD2) are antioxidant enzymes often overexpressed in tumors, including triple negative breast cancer (TNBC), making them promising targets for cancer therapy. Inhibiting these enzymes may worsen the already elevated oxidative stress in cancer cells, ultimately leading to cell death through a pro-oxidant mechanism. However, selectively targeting TXNRDs has been challenging due to the traditional reliance on covalent inhibition strategies. Recent studies have identified a druggable allosteric pocket in this enzyme family, paving the way for the development of novel non-covalent inhibitors, referred to as TXNRD(i)s. These inhibitors have been tested in TNBC models and have demonstrated a range of anti-cancer effects.</div><div>To understand the molecular and cellular consequences of TXNRD(i)s, we conducted unbiased transcriptomic analyses and found that the gene expression changes induced by TXNRD(i) treatment closely mirror those resulting from TXNRD1 silencing, reinforcing TXNRD1 as the primary therapeutic target. While TXNRD(i) treatment increases redox stress in TNBC cells, this is not the main driver of the anti-cancer effect. Instead, TXNRD(i)s potently inhibit cell proliferation and induce G1 phase cell cycle arrest. Notably, supplementing cells with exogenous deoxynucleotides restores cell viability, cell cycle progression and partially reverses cell death. These findings indicate that TXNRD(i)s impair ribonucleotide reductase activity and deplete endogenous deoxynucleotide pools as the main mechanism of anti-cancer effects. We further demonstrate that TXNRD(i)s inhibit both TXNRD1 and TXNRD2, and that dual inhibition is more effective in suppressing TNBC cell growth. <em>In vivo</em>, TXNRD(i) treatment significantly impairs TNBC xenograft tumor growth and reduces proliferation-related genes. Collectively, these findings challenge the prevailing paradigm that all TXNRD inhibitors function through a pro-oxidant mechanism, instead highlighting that non-covalent TXNRD(i)s exert their effects by blocking proliferation offering a compelling therapeutic strategy for TNBC and potentially other cancers with elevated TXNRD expression.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 103980"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784770","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":"Acetyl-CoA acyltransferase 2 palmitoylation drives liver fibrosis by inducing hepatic stellate cell ferroptosis","authors":"Jianxiong Han ,&nbsp;Zhongkang Yan ,&nbsp;Zhiran Sun ,&nbsp;Wenyuan Dang ,&nbsp;Bao Li ,&nbsp;Shuangshuang Li ,&nbsp;Xinru Lv ,&nbsp;Lin Ni ,&nbsp;Anyuan He ,&nbsp;Pengying Gu ,&nbsp;Feifei Wang ,&nbsp;Lili Wang ,&nbsp;Xingyuan Yang","doi":"10.1016/j.redox.2026.104035","DOIUrl":"10.1016/j.redox.2026.104035","url":null,"abstract":"<div><div>Hepatic fibrosis is a major driver of mortality in metabolic dysfunction-associated steatotic liver disease (MASLD)—previously known as non-alcoholic fatty liver disease (NAFLD). While hepatic stellate cell (HSC) activation and myofibroblast accumulation are central to fibrogenesis, the regulatory mechanisms remain incompletely understood. Acetyl-CoA acyltransferase 2 (ACAA2), a pivotal enzyme in fatty acid oxidation, has been implicated in lipid metabolism but has not been investigated as a therapeutic target in MASLD. Here, we show that ACAA2 upregulation in HSCs exacerbates hepatic fibrosis by promoting ferroptosis-associated transcriptional programs, whereas ACAA2 inhibition attenuates both ferroptosis and fibrogenesis in preclinical models. Mechanistically, ACAA2 palmitoylation governs its subcellular localization and function, and blocking this modification suppresses HSC activation via AMPK pathway stimulation, thereby mitigating fibrosis. Our study establishes ACAA2 palmitoylation as a druggable node for antifibrotic therapy, offering novel insights into metabolic regulation of hepatic fibrosis.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104035"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995154","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}