Abstract：
Hepatocellular carcinoma (HCC) is a malignant tumor that occurs in the liver, with a high degree of malignancy and relatively poor prognosis. Gypenoside L has inhibitory effects on liver cancer cells. However, its mechanism of action is still unclear. This study aims to investigate the inhibitory effects of gypenoside L on HCC in vitro and in vivo, and explore its potential mechanisms. The results showed that gypenoside L reduced the cholesterol and triglyceride content in HepG2 and Huh-7 cells, inhibited cell proliferation, invasion and metastasis, arrested cell cycle at G0/G1 phase, promoted cell apoptosis. Mechanistically, it targeted the transcription factor SREPB2 to inhibit the expression of HMGCS1 protein and inhibited the downstream proteins HMGCR and MVK, thereby regulating the mevalonate (MVA) pathway. Overexpression HMGCS1 led to significant alterations in the cholesterol metabolism pathway of HCC, which mediated HCC cell proliferation and conferred resistance to the therapeutic effect of gypenoside L. In vivo, gypenoside L effectively suppressed HCC growth in tumor-bearing mice by reducing cholesterol production, exhibiting favorable safety profiles and minimal toxic side effects. Gypenoside L modulated cholesterol homeostasis, enhanced expression of inflammatory factors by regulating MHC I pathway-related proteins to augment anticancer immune responses. Clinical samples from HCC patients also exhibited high expression levels of MVA pathway-related genes in tumor tissues. These findings highlight gypenoside L as a promising agent for targeting cholesterol metabolism in HCC while emphasizing the effectiveness of regulating the SREBP2-HMGCS1 axis as a therapeutic strategy.
摘要：
肝细胞癌（HCC）是一种发生在肝脏的恶性肿瘤，恶性程度高，预后相对较差。绞股蓝皂苷L对肝癌细胞有抑制作用。然而,其作用机制尚不清楚。本研究旨在探讨绞股蓝皂苷L对肝癌的体外和体内抑制作用。并探索其潜在机制。结果表明,绞股蓝皂苷L降低了HepG2和Huh-7细胞的胆固醇和甘油三酯含量,抑制细胞增殖，侵袭和转移，细胞周期停滞在G0/G1期，促进细胞凋亡。机械上,靶向转录因子SREPB2抑制HMGCS1蛋白的表达,抑制下游蛋白HMGCR和MVK,从而调节甲羟戊酸(MVA)途径。过表达HMGCS1导致HCC胆固醇代谢途径的显著改变，它介导HCC细胞增殖并赋予对绞股蓝皂苷L的治疗作用的抗性。绞股蓝皂苷L通过减少胆固醇产生有效抑制荷瘤小鼠肝癌生长，表现出良好的安全性和最小的毒副作用。绞股蓝皂苷L调节胆固醇稳态，通过调节MHCI途径相关蛋白增强炎症因子的表达以增强抗癌免疫应答。来自HCC患者的临床样品在肿瘤组织中也显示出MVA途径相关基因的高表达水平。这些发现强调了绞股蓝皂苷L作为靶向HCC胆固醇代谢的有前途的药物，同时强调了调节SREBP2-HMGCS1轴作为治疗策略的有效性。
