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

中医理论指出，抑郁、焦虑等情志异常可引发肝气郁结，推动肝细胞癌（hepatocellular carcinoma, HCC）的发生与进展，但其具体分子机制仍未明确。本研究依托大规模流行病学分析，探究了抑郁与肝细胞癌发病风险的关联，并对潜在生物学机制展开探索。研究分析了中国健康与养老追踪调查（China Health and Retirement Longitudinal Study, CHARLS；n=14770）及美国国家健康与营养检查调查（National Health and Nutrition Examination Survey, NHANES；n=29983）的数据集，对受试者的抑郁水平与肝细胞癌发病风险进行评估。结果显示，在CHARLS队列中，中度至重度抑郁者的肝细胞癌发病风险较无抑郁者显著升高（校正后风险比（hazard ratio, HR）=2.27；95%置信区间（confidence interval, CI）：1.05~4.91）；在NHANES队列中同样观察到显著关联（校正后优势比（odds ratio, OR）=5.96；95%CI：2.42~14.04）。荟萃分析结果表明，抑郁人群的肝细胞癌总体发病风险升高3.59倍（95%CI：1.40~9.24），且该结论在敏感性分析中保持稳健。基于上述发现，本研究采用社会隔离（social isolation, SI）模型，探究抑郁对肝细胞癌进展的影响。实验证实，社会隔离可显著加速自发性肝癌小鼠模型的肝细胞癌进展。机制层面，社会隔离可诱导肝细胞癌发生代谢重编程，表现为乳酸水平升高，进而使关键转录调控因子CBX5的蛋白表达及乳酸化水平上调。在转基因小鼠模型中，敲除Cbx5可减轻社会隔离相关的肝细胞癌进展。后续研究揭示，CBX5的K91位点乳酸化可增强其核转位能力，通过促进牛磺胆酸蓄积、与c-Myc形成复合物上调PHGDH以抑制铁死亡，最终促进肿瘤增殖。升高的牛磺胆酸可破坏RNF123与CBX5的相互作用，稳定肝细胞癌中的CBX5蛋白。为靶向调控该通路，本研究开发了一种新型H-PROTAC分子，该分子可有效降解CBX5、增强铁死亡并抑制肝细胞癌增殖，展现出潜在的临床治疗价值。综上，本研究揭示了抑郁与焦虑诱导的CBX5乳酸化在社会隔离模型中对肝细胞癌发生与进展的关键调控作用。上述发现为肝细胞癌的防治提供了全新视角，提示靶向CBX5的治疗方案在肝细胞癌治疗中具有重大应用潜力。整体研究设计：对肝癌组织与细胞中的社会隔离效应及CBX5的功能作用进行测序分析。