摘要
非酒精性脂肪性肝炎(NASH)是非酒精性脂肪性肝病(NAFLD)的晚期阶段,以肝细胞脂肪变性、炎症为核心特征,病情进展可引发肝纤维化、肝硬化和肝癌。法尼醇X受体(FXR)是一种在肝脏和肠道中高度表达、可被胆汁酸激活的核受体,其核心功能包括调节胆汁酸代谢、脂质合成相关基因表达,同时在抑制肝脏炎症、减轻纤维化及维持肠道微生态平衡中发挥关键作用,是NASH治疗的重要潜在靶点。目前有多个FXR激动剂正在进行临床试验,主要分为甾体类与非甾体类两大类。本文作者总结了FXR的主要生物学功能,以及小分子FXR激动剂在临床前研究和临床试验中的研究进展,以期为靶向FXR治疗NASH的药物研发提供参考。
Nonalcoholic steatohepatitis(NASH),the progressive form of non-alcoholic fatty liver disease(NAFLD),is characterized by hepatic steatosis and inflammation,which can progress to hepatic fibrosis,cirrhosis,and hepatocellular carcinoma.The farnesoid X receptor(FXR),a bile acid-activated nuclear receptor predominantly expressed in the liver and intestine,plays a pivotal role in regulating bile acid metabolism and lipid synthesis related gene expression,while also exerting critical functions in suppressing hepatic inflammation,alleviating fibrosis,and maintaining intestinal microecological homeostasis,thereby representing a key potential therapeutic target for NASH.Current investigational FXR agonists are categorized into steroidal derivatives and non-steroidal compounds,with several candidates advancing through clinical trials.In this review,the authors systematically summarize the main biological functions of FXR activation and the preclinical evidence and clinical trial outcomes of small-molecule FXR agonists,providing critical insights to guide the rational design of FXR-targeted therapies against NASH.
作者
朱元菊
程瑞雪
侯旭奔
方浩
ZHU Yuanju;CHENG Ruixue;HOU Xuben;FANG Hao(State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine,School of Pharmaceutical Sciences,Shandong University,Jinan 250012,China)
出处
《中国药物化学杂志》
2025年第6期468-479,共12页
Chinese Journal of Medicinal Chemistry
基金
国家科技重大专项项目(2023ZD0507700、2023ZD0507704)。
关键词
非酒精性脂肪肝炎
FXR激动剂
奥贝胆酸
Fibroblast growth factor receptor
(半空)Kinase
(半空)anti-tumor activity NASH
FXR agonists
obeticholic acid
