Farnesoid X receptor (FXR), a core member of the nuclear receptor (NR) superfamily, is a bile acid-activated nuclear transcription factor [1,2]. It is predominantly expressed in the liver and intestine, with lower levels detected in adipose tissue, vascular endothelium, and pancreas [3,4]. The NR superfamily comprises 48 members characterized by highly conserved domains [5]. As ligand-dependent transcriptional regulators, these receptors are responsible for governing a wide range of physiological processes, spanning from embryonic development to metabolic homeostasis [[6], [7], [8]]. Dysregulation of NRs is the underlying cause of various pathologies, including metabolic disorders (e.g., diabetes, obesity), malignancies, and hepatobiliary diseases. This makes the NR family a set of high-value therapeutic targets [9,10]. These multiple and complex roles of FXR confirm its potential as a clinical target for cholestatic and metabolic liver diseases, such as primary biliary cholangitis (PBC) and non-alcoholic steatohepatitis (NASH) [11,12].

While the development of FXR agonists has successfully translated the therapeutic promise of FXR for cholestatic and metabolic diseases into clinical reality, their clinical translation is hampered by significant dose-limiting systemic side effects. Given FXR's central role in metabolic regulation, agonist development has intensified since the discovery of GW4064 (∼2000) [13,14]. After two decades of research, multiple clinically advanced FXR agonists have emerged. Obeticholic acid (OCA, 1), the first FXR agonist approved for PBC treatment, established a novel therapeutic paradigm for bile acid disorders and became the first drug to enter Phase III trials for NASH [15,16] (Fig. 1A). Beyond bile acid derivatives (exemplified by OCA), structurally diverse agonists have progressed to clinical studies. Nevertheless, clinical application of FXR agonists faces significant challenges [17]. Despite well-defined mechanisms, systemic activation often causes dose-dependent adverse effects (such as pruritus, dyslipidemia, and drug-induced liver injury), limiting their long-term utility. Future efforts should prioritize developing tissue-selective agonists to improve therapeutic indices.

This review comprehensively examines FXR's structural biology and physiological functions, delineates its pathophysiological roles, and analyzes the design strategies, structure-activity relationships, and biological evaluation of FXR agonists. Current limitations are discussed, and future research directions are proposed to advance next-generation FXR-targeted therapeutics.