Psychological Stress Associated Bile Acid Reprogramming Promotes Hepatocellular Carcinoma Progression

Psychological stress, particularly depression, is increasingly recognized as a non‐genetic determinant of cancer progression, yet its role in hepatocellular carcinoma (HCC) remains unclear. 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) 1.06–4.93; NHANES: odds ratio (OR) = 5.95, 95% CI 2.42–14.0; UK Biobank: HR = 1.39, 95% CI 1.10–1.79). Using patient samples, multi‐omics analyses, and social isolation (SI) models, we identified taurocholate as a key metabolite elevated in psychological stress‐associated 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‐associated HCC models. Together, these findings support a mechanistic link between depression and HCC progression via bile acid metabolic reprogramming and identify the taurocholate‐CBX5‐MYC‐PHGDH axis as a potential therapeutic target.