FXR-targeted drug discovery: Recent advances and therapeutic perspectives

Farnesoid X Receptor (FXR), a pivotal member of the nuclear receptor superfamily, plays a central role in the regulation of crucial physiological processes. These processes encompass bile acid homeostasis, inflammatory responses, fibrosis, as well as lipid and glucose metabolism. Given its extensive physiological functions, FXR has become an extremely promising therapeutic target for bile acid metabolism disorders. In recent years, the progress in medicinal chemistry has significantly expedited the development of FXR agonists. In 2016, obeticholic acid (OCA) received approval from FDA for marketing. As the first small-molecule drug targeting FXR for primary biliary cholangitis (PBC), its approval has spurred the advancement of multiple FXR agonists with diverse chemical structures into clinical trials. Notable candidates include Tropifexor (for non-alcoholic steatohepatitis, NASH), Cilofexor (for PBC), and Nidufexor (for diabetic nephropathy). This review delineates the structural features and biological functions of FXR, analyzes molecular mechanisms underpinning its signal transduction pathways and disease pathogenesis, and highlights molecular design strategies and structure-activity relationship (SAR) advancements in FXR agonists. These insights aim to provide a theoretical foundation for rationally designing novel, potent FXR agonists.