Depression and Anxiety-Induced Metabolic Reprogramming Promotes Hepatocellular Carcinoma Progression through CBX5 Lactylation: Involvement of Taurocholate and PHGDH-Mediated Ferroptosis
Traditional Chinese medicine posits that emotional disorders like depression and anxiety can lead to liver qi stagnation, promoting the occurrence and progression of hepatocellular carcinoma (HCC). However, the specific mechanisms remain unclear. This study investigated the association between depression and HCC risk through large-scale epidemiological analyses, and the underlying biological mechanisms were explored. Data were analyzed from the China Health and Retirement Longitudinal Study (CHARLS; n = 14,770) and the National Health and Nutrition Examination Survey (NHANES; n = 29,983), assessing depression levels and HCC risk. Participants with moderate to severe depression had a significantly increased risk of HCC compared to those without depression in both CHARLS (adjusted hazard ratio [HR] = 2.27; 95% confidence interval [CI]: 1.05–4.91) and NHANES (adjusted odds ratio [OR] = 5.96; 95% CI: 2.42–14.04). A meta-analysis indicated an overall 3.59-fold increased risk of HCC (95% CI: 1.40–9.24) among depressed participants. These findings remained robust across sensitivity analyses. Building on these results, a social isolation (SI) model was employed to study the impact of depression on HCC progression. SI significantly accelerated HCC progression in a spontaneous tumor mouse model. Mechanistically, social isolation drove metabolic reprogramming in HCC, characterized by elevated lactate levels, which in turn led to increased protein expression and lactylation of one of the key transcriptional regulators, CBX5. Knockout of Cbx5 attenuated the progression of HCC associated with social isolation in the transgenic mouse model. Then, it was shown that lactylation of CBX5 at the K91 site enhances its nuclear translocation, promoting tumor proliferation through enhancing the accumulation of taurocholate and upregulating PHGDH via forming a complex with c-Myc to inhibit ferroptosis. The elevated taurocholate disrupted the interaction between RNF123 and CBX5, stabilizing CBX5 in HCC. To target this pathway, a novel H-PROTAC molecule was developed that effectively degrades CBX5, enhances ferroptosis, and inhibits HCC proliferation, demonstrating potential therapeutic value. In conclusion, the study reveals the critical role of depression and anxiety-induced CBX5 lactylation in HCC occurrence and progression within a social isolation model. These findings provide new insights into HCC prevention and treatment, suggesting that CBX5-targeted therapies hold significant potential for HCC treatment. Overall design: Sequencing analysis of social isolation and the role of CBX5 in liver cancer tissues and cells