Tian Dianzhe, Jiang Shitao, Liu Yaoge, Zheng Han, Zhang Lei, Xu Yiyao, Lu Xin
Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China.
Eight-year Medical Doctor Program, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Discov Oncol. 2025 Jun 2;16(1):987. doi: 10.1007/s12672-025-02321-9.
Dysregulation of cholesterol metabolism has been recognized as a critical driver in the pathogenesis of hepatic disorders, particularly hepatocellular carcinoma (HCC) and metabolic dysfunction-associated steatotic liver disease (MASLD). However, the causal relationships between circulating proteins involved in cholesterol homeostasis and the progression of these hepatopathologies remain insufficiently explored, warranting further mechanistic investigation.
This study utilized Mendelian randomization (MR) to identify the role of cholesterol metabolism-related proteins in HCC and MASLD. We systematically investigated the causal associations of these proteins with HCC and MASLD and their roles in disease progression using circulating proteomic databases and bioinformatics tools. In addition, network-based drug repositioning techniques and molecular docking experiments were utilized to assess the interactions of the above biomarkers with known drugs to discover drugs with potential therapeutic effects.
MR analysis identified several proteins linked with significant risk for HCC and MASLD. Notably, apolipoprotein E (APOE) expression was significantly increased in tissues from HCC and MASLD patients, closely correlating with elevated disease risk. Meta-analysis demonstrated a significant causal relationship between APOE and increased risk of HCC (OR: 1.710, 95% CI 1.220-2.400; P < 0.01) and MASLD (OR: 1.490, 95% CI 1.280-1.740; P < 0.01). Additionally, network analysis revealed extensive interactions between APOE and other disease-related proteins, suggesting that APOE may contribute to liver disease progression through its influence on complex protein networks.
Our findings delineate a novel mechanistic involvement of cholesterol regulatory proteins, with APOE demonstrating pathogenic significance in both HCC and MASLD. This investigation substantially provides new insights into the molecular mechanisms of these liver diseases and highlights potential therapeutic targets.
胆固醇代谢失调已被认为是肝脏疾病发病机制中的关键驱动因素，尤其是肝细胞癌（HCC）和代谢功能障碍相关脂肪性肝病（MASLD）。然而，参与胆固醇稳态的循环蛋白与这些肝脏疾病进展之间的因果关系仍未得到充分探索，需要进一步进行机制研究。
本研究利用孟德尔随机化（MR）来确定胆固醇代谢相关蛋白在HCC和MASLD中的作用。我们使用循环蛋白质组数据库和生物信息学工具，系统地研究了这些蛋白与HCC和MASLD的因果关联及其在疾病进展中的作用。此外，利用基于网络的药物重新定位技术和分子对接实验来评估上述生物标志物与已知药物的相互作用，以发现具有潜在治疗作用的药物。
MR分析确定了几种与HCC和MASLD显著风险相关的蛋白。值得注意的是，载脂蛋白E（APOE）在HCC和MASLD患者的组织中表达显著增加，与疾病风险升高密切相关。荟萃分析表明，APOE与HCC风险增加（OR：1.710，95%CI 1.220 - 2.400；P < 0.01）和MASLD风险增加（OR：1.490，95%CI 1.280 - 1.740；P < 0.01）之间存在显著的因果关系。此外，网络分析揭示了APOE与其他疾病相关蛋白之间的广泛相互作用，表明APOE可能通过影响复杂的蛋白质网络促进肝脏疾病进展。
我们的研究结果描绘了胆固醇调节蛋白的一种新的机制参与，APOE在HCC和MASLD中均显示出致病意义。这项研究为这些肝脏疾病的分子机制提供了重要的新见解，并突出了潜在的治疗靶点。
