肝细胞癌（HCC）是一种常见的恶性肿瘤，具有较高的发病率和死亡率。靶向异常的胆固醇代谢是一种潜在的治疗方向。因此，需要开发更多针对HCC中胆固醇的自然药物。葛根苷（Gyp）是绞股蓝主要成分之一，已被证明具有抗癌、抗肥胖和肝保护的药理特性。我们研究了由我们实验室分离纯化的Gyp是否能通过抑制胆固醇合成抑制HCC的进展。本研究表明，Gyp抑制了Huh-7和Hep3B细胞的增殖和迁移，并诱导了细胞凋亡。代谢组学、转录组学和靶点预测均表明，脂质代谢和胆固醇生物合成是Gyp的机制。Gyp可以限制胆固醇的产生并靶向胆固醇合成相关蛋白HMGCS1。HMGCS1的下调可以抑制HCC的进展和异常胆固醇代谢。在机制方面，Gyp通过抑制HMGCS1转录因子SREBP2抑制了甲萘酸（MVA）途径介导的胆固醇合成。而HCC人体标本中HMGCS1的高表达与不良临床预后相关。数据表明，Gyp可能是一种有前景的降低胆固醇药物，用于HCC的预防和治疗。并且靶向MVA途径中的SREBP2-HMGCS1轴可能是一种有效的HCC治疗策略。版权所有 © 2023 Elsevier B.V.出版。

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with high morbidity and mortality. Targeting abnormal cholesterol metabolism is a potential therapeutic direction. Therefore, more natural drugs targeting cholesterol in HCC need to be developed. Gypenosides (Gyp), the major constituent of Gynostemma pentaphyllum, has been demonstrated to have pharmacological properties on anti-cancer, anti-obesity, and hepatoprotective. We investigated whether Gyp, isolated and purified by our lab, could inhibit HCC progression by inhibiting cholesterol synthesis. The present research showed that Gyp inhibited proliferation and migration, and induced apoptosis in Huh-7 and Hep3B cells. Metabolomics, transcriptomics, and target prediction all suggested that lipid metabolism and cholesterol biosynthesis were the mechanisms of Gyp. Gyp could limit the production of cholesterol and target HMGCS1, the cholesterol synthesis-related protein. Downregulation of HMGCS1 could suppress the progression and abnormal cholesterol metabolism of HCC. In terms of mechanism, Gyp suppressed mevalonate (MVA) pathway mediated cholesterol synthesis by inhibiting HMGCS1 transcription factor SREBP2. And the high expression of HMGCS1 in HCC human specimens was correlated with poor clinical prognosis. The data suggested that Gyp could be a promising cholesterol-lowering drug for the prevention and treatment of HCC. And targeting SREBP2-HMGCS1 axis in MVA pathway might be an effective HCC therapeutic strategy.Copyright © 2023. Published by Elsevier B.V.