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By integrating three prospective cohorts (CHARLS, NHANES, and UK Biobank; n = 492,501), we show that depression was associated with increased HCC risk (CHARLS: hazard ratio (HR) = 2.28, 95% confidence interval (CI) 1.06\u20134.93; NHANES: odds ratio (OR) = 5.95, 95% CI 2.42\u201314.0; UK Biobank: HR = 1.39, 95% CI 1.10\u20131.79). Using patient samples, multi\u2010omics analyses, and social isolation (SI) models, we identified taurocholate as a key metabolite elevated in psychological stress\u2010associated HCC. Taurocholate stabilizes CBX5 by weakening its interaction with E3 ubiquitin ligases. CBX5 cooperated with MYC to activate PHGDH transcription, thereby reducing ferroptotic sensitivity and promoting tumor growth. Importantly, ursodeoxycholic acid (UDCA), a clinically approved bile acid modulator, reduced taurocholate levels and suppressed tumor growth in SI\u2010associated HCC models. Together, these findings support a mechanistic link between depression and HCC progression via bile acid metabolic reprogramming and identify the taurocholate\u2010CBX5\u2010MYC\u2010PHGDH axis as a potential therapeutic target.<\/jats:p>","DOI":"10.1002\/advs.76416","type":"journal-article","created":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T22:31:11Z","timestamp":1783809071000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Psychological Stress Associated Bile Acid Reprogramming Promotes Hepatocellular Carcinoma Progression"],"prefix":"10.1002","volume":"13","author":[{"given":"Ruijiang","family":"Zeng","sequence":"first","affiliation":[{"name":"Department of Urology The Second Xiangya Hospital Central South University  Changsha Hunan China"},{"name":"Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education National Clinical Research Center for Metabolic Disease  Changsha China"},{"name":"Uro\u2010Oncology Institute of Central South University  Changsha Hunan China"},{"name":"Hunan Key Laboratory of Tumor Models and Individualized Medicine The Second Xiangya Hospital Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengmeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Cancer Center, Union Hospital, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology The First Affiliated Hospital of University of South China  Hengyang P. 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