The State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, 361005, China.
Acta Pharmacol Sin. 2022 May;43(5):1120-1132. doi: 10.1038/s41401-021-00849-4. Epub 2022 Feb 25.
The nuclear receptor farnesoid-X-receptor (FXR) plays an essential role in bile acid, glucose, and lipid homeostasis. In the last two decades, several diseases, such as obesity, type 2 diabetes, nonalcoholic fatty liver disease, cholestasis, and chronic inflammatory diseases of the liver and intestine, have been revealed to be associated with alterations in FXR functions. FXR has become a promising therapeutic drug target, particularly for enterohepatic diseases. Despite the large number of FXR modulators reported, only obeticholic acid (OCA) has been approved for primary biliary cholangitis (PBC) therapy as FXR modulator. In this review, we summarize the structure and function of FXR, the development of FXR modulators, and the structure-activity relationships of FXR modulators. Based on the structural analysis, we discuss potential strategies for developing future therapeutic FXR modulators to overcome current limitations, providing new perspectives for enterohepatic and metabolic diseases treatment.
核受体法尼醇 X 受体（FXR）在胆汁酸、葡萄糖和脂质稳态中发挥着重要作用。在过去的二十年中，几种疾病，如肥胖症、2 型糖尿病、非酒精性脂肪性肝病、胆汁淤积、以及肝和肠的慢性炎症性疾病，都被揭示与 FXR 功能的改变有关。FXR 已成为一种有前途的治疗药物靶点，特别是针对肝胆疾病。尽管已经报道了大量的 FXR 调节剂，但只有奥贝胆酸（OCA）被批准作为 FXR 调节剂用于原发性胆汁性胆管炎（PBC）的治疗。在这篇综述中，我们总结了 FXR 的结构和功能、FXR 调节剂的发展以及 FXR 调节剂的构效关系。基于结构分析，我们讨论了开发未来治疗性 FXR 调节剂的潜在策略，以克服当前的限制，为肝胆和代谢性疾病的治疗提供新的视角。
