番泻苷B作为潜在FASN抑制剂在MASH治疗中的药物再利用研究

Drug Repurposing Study of Sennoside B as a Potential FASN Inhibitor for the Treatment of MASH

摘要: 脂肪酸合酶(Fatty Acid Synthase, FASN)在脂质合成中发挥关键作用，肝脏中的FASN异常激活是代谢功能障碍相关脂肪性肝炎(Metabolic Dysfunction-Associated Steatohepatitis, MASH)发病的重要因素之一。本研究基于药物再利用策略，采用虚拟筛选和体外实验相结合的方法，从已批准通过I期临床试验的药物中筛选潜在FASN抑制剂进而开发新型MASH药物。经虚拟筛选得到番泻苷B具有较强的FASN抑制潜力，体外实验表明，其可显著降低MASH细胞模型中的甘油三酯和谷草转氨酶水平，并且能够下调FASN和SREBP1等脂质合成相关基因表达，上调CPT1A和ACOX1等脂肪酸氧化相关基因表达。分子动力学模拟进一步验证了其与FASN蛋白结合稳定。因此，番泻苷B能够通过抑制FASN调控脂质代谢，具有作为MASH治疗候选药物的开发潜力。

Abstract: Fatty acid synthase (FASN) plays a pivotal role in lipid biosynthesis, and its aberrant activation in the liver is one of the key pathogenic factors contributing to metabolic dysfunction-associated steatohepatitis (MASH). In this study, based on a drug repurposing strategy, a combination of virtual screening and in vitro experiments was employed to identify potential FASN inhibitors from drugs that have already passed Phase I clinical trials, aiming to develop novel therapeutic agents for MASH. Through virtual screening, Sennoside B was identified as a promising FASN inhibitor. Subsequent in vitro assays demonstrated that Sennoside B significantly reduced triglyceride and aspartate aminotransferase levels in a MASH cell model. Moreover, it was shown to downregulate the expression of lipid synthesis-related genes, such as FASN and SREBP1, while upregulating fatty acid oxidation-related genes, including CPT1A and ACOX1. Molecular dynamics simulations further confirmed the stable binding of Sennoside B to the FASN protein. Therefore, Sennoside B may regulate lipid metabolism by inhibiting FASN, demonstrating promising potential as a candidate therapeutic agent for MASH.