Cell Chemical BiologyPub Date : 2026-08-20Epub Date: 2026-07-07DOI: 10.1016/j.chembiol.2026.06.001
Wei Wang, Linmeng Zhang, Qiaozhu Zuo, Xuhui Ma, Ying Cao, Lili Zhu, Shuyi Ji, Wenxin Qin, Hui Wang, Shengxian Yuan, René Bernards, Cun Wang
{"title":"XPO1 inhibition induces NCOR1-Dependent oxidative stress to suppress hepatocellular carcinoma","authors":"Wei Wang, Linmeng Zhang, Qiaozhu Zuo, Xuhui Ma, Ying Cao, Lili Zhu, Shuyi Ji, Wenxin Qin, Hui Wang, Shengxian Yuan, René Bernards, Cun Wang","doi":"10.1016/j.chembiol.2026.06.001","DOIUrl":"10.1016/j.chembiol.2026.06.001","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to the limited efficacy of current systemic therapies. To identify potential therapeutic approaches, computational analysis of HCC datasets and drug screening were integrated, leading to the repurposing of hematological malignancy drug selinexor (an XPO1 inhibitor) for HCC treatment. Functional studies revealed that XPO1 inhibition triggers oxidative stress and cell cycle arrest in HCC cells through nuclear sequestration of NCOR1, disrupting redox homeostasis through FOXK1-dependent transcriptional activation of genes associated with reactive oxygen species (ROS). A genome-wide CRISPR-Cas9 screen further identified the KEAP1-NRF2 axis as a key determinant of sensitivity to XPO1 inhibition. Furthermore, high-throughput compound screening demonstrated that disulfiram, a clinically used aldehyde dehydrogenase inhibitor, synergizes with XPO1 inhibitor through exacerbation of ROS accumulation. Collectively, these findings demonstrate the therapeutic repurposing of selinexor for HCC while uncovering its mechanism of action, establishing a predictive biomarker, and proposing an immediately translatable combination therapy.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 8","pages":"Pages 1205-1216.e6"},"PeriodicalIF":9.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403009","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}
Cell Chemical BiologyPub Date : 2026-08-20Epub Date: 2026-07-28DOI: 10.1016/j.chembiol.2026.06.017
Ge-Xin Zhao (赵舸昕), Xin-Yan Fang (房昕燕), Ting Li (李婷), Guo-Long Bu (卜国龙), Jing Wang (王静), Wen-Ting Du (杜文婷), Pei-Huang Wu (吴培煌), Hang Zhou (周杭), Guo-Kai Feng (冯国开), Sen-Fang Sui (隋森芳), Cong Sun (孙聪), Zheng Liu (刘铮), Mu-Sheng Zeng (曾木圣)
{"title":"A protective human antibody reveals a quaternary epitope on the Epstein-Barr virus fusion apparatus","authors":"Ge-Xin Zhao (赵舸昕), Xin-Yan Fang (房昕燕), Ting Li (李婷), Guo-Long Bu (卜国龙), Jing Wang (王静), Wen-Ting Du (杜文婷), Pei-Huang Wu (吴培煌), Hang Zhou (周杭), Guo-Kai Feng (冯国开), Sen-Fang Sui (隋森芳), Cong Sun (孙聪), Zheng Liu (刘铮), Mu-Sheng Zeng (曾木圣)","doi":"10.1016/j.chembiol.2026.06.017","DOIUrl":"10.1016/j.chembiol.2026.06.017","url":null,"abstract":"<div><div>Epstein-Barr virus (EBV) entry into B lymphocytes and epithelial cells requires the conserved fusion machinery gHgL and the tropism-switching glycoprotein gp42. While the individual roles of these proteins have been extensively studied, the functional contribution and antibody accessibility of the assembled gHgL-gp42 complex remain unclear. Here, we describe a human monoclonal antibody, 4G12, that selectively recognizes this complex by binding a quaternary epitope spanning the gHgL DII domain and the gp42 N-terminal interface. 4G12 potently neutralizes EBV infection in both B cells and epithelial cells by blocking viral binding and membrane fusion. A cryogenic electron microscopy (cryo-EM) structure reveals a vulnerable site within the fusion apparatus and defines the molecular basis of inhibition. Importantly, 4G12 confers robust protection against EBV challenge in humanized mice. These findings identify a neutralizing epitope on the gHgL-gp42 fusion complex and establish 4G12 as a mechanistic probe and candidate for EBV prophylaxis.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 8","pages":"Pages 1135-1145.e7"},"PeriodicalIF":9.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597180","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}
Cell Chemical BiologyPub Date : 2026-08-20Epub Date: 2026-06-08DOI: 10.1016/j.chembiol.2026.05.004
Sujyoti Chandra, Chulhwan S. Kwak, Zehui Du, Giuseppe Barisano, Kong T. Nguyen, Vlad Vinogradov, Xinnan Wang
{"title":"Chemical modulation of Miro1 alleviates cell-type-specific vulnerabilities in Friedreich’s ataxia","authors":"Sujyoti Chandra, Chulhwan S. Kwak, Zehui Du, Giuseppe Barisano, Kong T. Nguyen, Vlad Vinogradov, Xinnan Wang","doi":"10.1016/j.chembiol.2026.05.004","DOIUrl":"10.1016/j.chembiol.2026.05.004","url":null,"abstract":"<div><div>Friedreich’s ataxia (FA) is marked by early-onset sensory neurodegeneration and cardiomyopathy. We establish a human dual-cell model of FA by differentiating sensory neurons and cardiomyocytes from the same patients, enabling parallel molecular profiling of disease-relevant cell types. Proteomic analysis reveals distinct, cell-type-specific pathway disruptions in response to frataxin deficiency. Leveraging this platform, we investigate Miro1 reducer 3 (MR3), a selective chemical probe binding Miro1, a mitochondrial outer membrane protein implicated in redox regulation in FA. MR3 treatment modulates molecular signatures in a cell-type-dependent manner, altering pathways related to cardiac contractility in cardiomyocytes and synaptic function in sensory neurons. Mechanistically, MR3 reduces mitochondrial reactive oxygen species and restores membrane potential in FA sensory neurons via potential allosteric reshaping of Miro1 protein. We expand the chemical diversity of this scaffold by conducting ligand-based virtual screening of over 3 billion compounds and identifying previously uncharacterized Miro1 ligands with improved docking and neuroprotective capacity.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 8","pages":"Pages 1193-1204.e12"},"PeriodicalIF":9.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148203470","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}
Lin Song Kretschmer, Dominique C. Mitchell, Jin Liu, Logan Leak, Rigney E. Turnham, LeeAnn Wang, Zheng Wang, Changliang He, Luo Ding, Marc Adler, Timothy Kellett, Aidan Keith, Yeonjoo C. Hwang, Gary K.L. Chan, Robert L.G. Gottschalk, Weicheng Li, Lieza M. Chan, Roopa Ramamoorthi, Sarah Lively, Robert A. Drakas, Vijay Ramani, Tingting Qing, Kliment A. Verba, Trever Bivona, Jonathan M.L. Ostrem, Richard T. Beresis, John D. Gordan
{"title":"Small-molecule activation of the tumor suppressor kinase LKB1 via the pseudokinase STRAD","authors":"Lin Song Kretschmer, Dominique C. Mitchell, Jin Liu, Logan Leak, Rigney E. Turnham, LeeAnn Wang, Zheng Wang, Changliang He, Luo Ding, Marc Adler, Timothy Kellett, Aidan Keith, Yeonjoo C. Hwang, Gary K.L. Chan, Robert L.G. Gottschalk, Weicheng Li, Lieza M. Chan, Roopa Ramamoorthi, Sarah Lively, Robert A. Drakas, Vijay Ramani, Tingting Qing, Kliment A. Verba, Trever Bivona, Jonathan M.L. Ostrem, Richard T. Beresis, John D. Gordan","doi":"10.1016/j.chembiol.2026.07.013","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.07.013","url":null,"abstract":"","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"21 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148756508","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}
Zainab Edoo, Astrid Lenne-Delmotte, Camille Grosse, Marie Devaere, Marion Michel, Guillaume Caron, Ernesto Anoz-Carbonell, Kamel Djaout, Rosangela Frita, Cyril Gaudin, Line Hofmann, Sophie Lecher, Véronique Megalizzi, Alessia Michelotti, David Rengel, Pauline Rouan, Stephanie Slupek, Lina Tawk, Rudy Antoine, Hanna Kulyk, Glenn Dale, Christophe Guilhot, Nicolas Willand, Guy Lippens, René Wintjens, Alain R Baulard
{"title":"BVL3572S inhibits HisC and AlaA, exploiting vitamin B6 dependency to kill Mycobacterium tuberculosis.","authors":"Zainab Edoo, Astrid Lenne-Delmotte, Camille Grosse, Marie Devaere, Marion Michel, Guillaume Caron, Ernesto Anoz-Carbonell, Kamel Djaout, Rosangela Frita, Cyril Gaudin, Line Hofmann, Sophie Lecher, Véronique Megalizzi, Alessia Michelotti, David Rengel, Pauline Rouan, Stephanie Slupek, Lina Tawk, Rudy Antoine, Hanna Kulyk, Glenn Dale, Christophe Guilhot, Nicolas Willand, Guy Lippens, René Wintjens, Alain R Baulard","doi":"10.1016/j.chembiol.2026.07.008","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.07.008","url":null,"abstract":"<p><p>Tuberculosis remains the leading cause of death from a single infectious agent, and rising multi-drug resistance in Mycobacterium tuberculosis (Mtb) underscores the urgent need for new antibiotics. Here, we characterize BVL3572S, a hydroxamic acid-containing compound that is bactericidal against Mtb. The primary targets of BVL3572S are the pyridoxal phosphate (PLP; active form of vitamin B6)-dependent aminotransferases HisC (Rv1600) and AlaA (Rv0337c; formerly AspC), simultaneously impacting L-histidine and L-alanine biosynthesis. X-ray crystallography revealed a covalent PLP-BVL3572S adduct within the HisC active site. The formation of the adduct followed by its release suggests a futile cycle that depletes PLP. Consistently, isotopic labeling revealed widespread perturbation of amino acid biosynthesis. CRISPRi and Tn-seq analyses additionally indicated disruptions in central metabolism, cell envelope integrity, and redox balance. BVL3572S displayed strong synergy with the antitubercular drug D-cycloserine. Collectively, our findings establish BVL3572S as a promising lead compound acting through a previously unexploited, multitarget mechanism.</p>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148710967","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}
Shusheng Wang, Omid Tavassoly, Morshed A Chowdhury, Leanne Carter, Devin Brown, Rodrigo Carasco Bravo, Anshita Madaan, Ziyang Zhang, Daniel Tesolin, Maa O Quartey, Benjamin Pluvinage, Jennifer N Nyarko, Manoj Kumar, Julia Vander Velde, Zishuo Xu, Ricardo A Feldman, Alisdair B Boraston, Darrell D Mousseau, Aarnoud C van der Spoel, Christopher P Phenix
{"title":"Chemical tools for inhibition and activity-based profiling of glucocerebrosidase in vitro and in vivo.","authors":"Shusheng Wang, Omid Tavassoly, Morshed A Chowdhury, Leanne Carter, Devin Brown, Rodrigo Carasco Bravo, Anshita Madaan, Ziyang Zhang, Daniel Tesolin, Maa O Quartey, Benjamin Pluvinage, Jennifer N Nyarko, Manoj Kumar, Julia Vander Velde, Zishuo Xu, Ricardo A Feldman, Alisdair B Boraston, Darrell D Mousseau, Aarnoud C van der Spoel, Christopher P Phenix","doi":"10.1016/j.chembiol.2026.07.007","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.07.007","url":null,"abstract":"<p><p>Deficiencies in glucocerebrosidase (GCase) are associated with Parkinson's disease (PD). The mechanistic basis of this association is being intensively investigated, and new treatments are being developed aiming to boost brain GCase activity in patients. Despite the importance of GCase in PD, studies are hampered by the continued reliance on weak and non-selective inhibitors like conduritol B epoxide. Here, we report easily prepared and selective irreversible inhibitors and complementary fluorescent activity-based probes (ABPs), along with straightforward methods to inhibit and/or monitor GCase activity. Robust characterization shows that compound CAz-5c selectively inactivates GCase in vitro, in live cells, and in vivo-including GCase in the brains of live mice, at low doses, overcoming a limitation of previously reported inhibitors. Collectively, these tools can be used to generate titratable chemical models of neuropathic GCase deficiency in animals with various genetic backgrounds with unrivaled molecular precision.</p>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148704912","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}
Cong Li, Qiaohua Yan, Muhammad Muddasar Saeed, Yubin Luo, Peidu Jiang, Qingxiang Sun
{"title":"Repurposing simeprevir uncovers a druggable KPNB1-p65-BCL2 survival axis in cancer.","authors":"Cong Li, Qiaohua Yan, Muhammad Muddasar Saeed, Yubin Luo, Peidu Jiang, Qingxiang Sun","doi":"10.1016/j.chembiol.2026.07.005","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.07.005","url":null,"abstract":"<p><p>Proper subcellular protein localization is fundamental for protein function, yet cancer cells often exploit this machinery for survival. While the nuclear import receptor KPNB1 (importin β1) is overexpressed in various cancers, its oncogenic mechanisms remain incompletely understood and its therapeutic targeting remains in infancy. Through screening of an FDA-approved compound library, we uncovered simeprevir (Sim) and lusutrombopag (Lus) as direct KPNB1 inhibitors that disrupt its import complex assembly. These compounds blocked KPNB1-mediated nuclear import of p65, thereby suppressing Bcl-2 transcription and activating mitochondrial apoptosis. Overexpression of KPNB1, p65, or Bcl-2, but not nuclear localization signal (NLS)-deleted p65, reversed the effect of Sim/Lus. Sim induced apoptosis in multiple cancer cell lines by downregulating Bcl-2 expression and suppressed A549 xenografts growth without observable toxicity. Analysis of The Cancer Genome Atlas (TCGA) datasets substantiated the clinical relevance of the KPNB1-p65-Bcl-2 axis. Our study elucidates a therapeutically targetable KPNB1-p65-Bcl-2 survival axis in multiple cancers and establishes a foundation for developing next-generation KPNB1 inhibitors.</p>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648194","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}
Logan Elkin, Evgeny G Chulkov, Jonathan D Enders, Anthony D Menzel, Sang-Kyu Park, Cheryl L Stucky, Jonathan S Marchant
{"title":"TRPM8 is a non-canonical target of 7-nitrobenzodiazepines.","authors":"Logan Elkin, Evgeny G Chulkov, Jonathan D Enders, Anthony D Menzel, Sang-Kyu Park, Cheryl L Stucky, Jonathan S Marchant","doi":"10.1016/j.chembiol.2026.06.018","DOIUrl":"10.1016/j.chembiol.2026.06.018","url":null,"abstract":"<p><p>Benzodiazepines are widely prescribed therapeutics whose actions are primarily attributed to the modulation of GABA<sub>A</sub> receptors. Here, we identify a previously unrecognized target of a subset of benzodiazepines-the cold- and menthol-sensitive ion channel TRPM8 (transient receptor potential melastatin 8). Clonazepam and related 7-nitrobenzodiazepines act as potent TRPM8 agonists, eliciting calcium influx and membrane depolarization in heterologous expression systems, native human cells, and trigeminal sensory neurons. Pharmacological inhibition, genetic knockdown, and gene deletion of TRPM8 abolish clonazepam-evoked responses, establishing TRPM8 as the relevant molecular target. Mechanistically, clonazepam shares pharmacological features with icilin, a canonical TRPM8 agonist, and engages conserved determinants of channel activation. These findings expand the pharmacology of benzodiazepines beyond GABA<sub>A</sub> receptors and suggest that TRPM8 activation may contribute to the clinical efficacy of clonazepam in burning mouth disorder and other sensory neuropathic conditions.</p>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13426060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148617737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hanzhong Feng, Hang Xu, Zhuangzhuang Chu, Xuelin Li, Jun Hou, Jiarong Wang, Hang Xu, Haonan Cao, Wei Ming, Hao Yang, Xinxiang Lei, Yong-Xing He
{"title":"Multinuclear iron enzymes expand RiPP chemical diversity to enable bacterial oxidative stress defense.","authors":"Hanzhong Feng, Hang Xu, Zhuangzhuang Chu, Xuelin Li, Jun Hou, Jiarong Wang, Hang Xu, Haonan Cao, Wei Ming, Hao Yang, Xinxiang Lei, Yong-Xing He","doi":"10.1016/j.chembiol.2026.06.014","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.06.014","url":null,"abstract":"<p><p>RiPP structural complexity is significantly expanded by multinuclear non-heme iron-dependent oxidative enzymes (MNIOs). Here, we characterize pseudoprobactin 1 and 2, two MNIO-modified proteins from Pseudomonas protegens Pf-5. Using MS, NMR, and X-ray crystallography, we show that the PbnBC converts precursor cysteines into 5-thiooxazoles. While the precursors feature an N-terminal signal peptide and an intramolecular disulfide, both are dispensable for catalysis. Instead, residues downstream of the target cysteines are the primary determinants of substrate recognition. Furthermore, PbnB2C2 modifies multiple sites in a strictly ordered, stepwise manner. Functionally, pseudoprobactins coordinate Cu<sup>2+</sup>, enhancing bacterial fitness under chlorite-induced oxidative stress. This work establishes 5-thiooxazole as a widespread MNIO-mediated modification, defines its biosynthetic logic, and reveals a role for MNIO-modified proteins in bacterial oxidative stress defense.</p>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597120","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}
Xiutao Cai, Fangquan Chen, Ruirui Liang, Hu Tang, Qile Zhou, Junhao Lin, Rui Kang, Daolin Tang, Jiao Liu
{"title":"The pyruvate dehydrogenase complex at the crossroads of cancer metabolism and cell death","authors":"Xiutao Cai, Fangquan Chen, Ruirui Liang, Hu Tang, Qile Zhou, Junhao Lin, Rui Kang, Daolin Tang, Jiao Liu","doi":"10.1016/j.chembiol.2026.06.009","DOIUrl":"10.1016/j.chembiol.2026.06.009","url":null,"abstract":"<div><div>The pyruvate dehydrogenase complex (PDHC) is a key metabolic hub that couples glycolysis-derived carbon flux to the tricarboxylic acid cycle and mitochondrial function. Its activity is regulated by pyruvate dehydrogenase kinases, phosphatases, and lysine acylation, enabling dynamic responses to metabolic and stress signals. In cancer, dysregulation of the PDK-PDHC axis reduces PDH flux, promotes aerobic glycolysis, and enhances adaptation to mitochondrial and oxidative stress, thereby influencing susceptibility to regulated cell death. Recent studies further suggest that PDHC exhibits considerable structural and functional plasticity under hypoxia and redox stress. Growing preclinical and translational evidence indicates that targeting the PDK-PDHC axis may redirect metabolic flux and improve therapeutic responses in selected tumor contexts. This review summarizes current understanding of PDHC regulation, its context-dependent roles in regulated cell death, and the therapeutic potential and challenges of exploiting PDH-related metabolic vulnerabilities in cancer.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 7","pages":"Pages 966-981"},"PeriodicalIF":9.0,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148461563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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