NR1H4 (farnesoid X receptor/FXR) is a nuclear bile acid receptor that functions as a ligand-activated transcription factor critical for hepatic homeostasis 1. It promotes transcriptional activation of genes encoding bile acid transporters (ABCB11/BSEP, SLC51B/OSTB) and regulatory factors (NR0B2/SHP, FABP6/IBAP), with activation occurring through unconjugated bile acids such as chenodeoxycholic acid and deoxycholic acid 2. NR1H4 regulates energy metabolism across liver, muscle, and adipose tissues and maintains hepatic stellate cell quiescence through integration of postprandial bile acid signals 3. Loss-of-function NR1H4 mutations cause progressive familial intrahepatic cholestasis type 5 (PFIC5), characterized by impaired bile acid-dependent transcriptional regulation and accumulation of toxic bile acids in hepatocytes 145. In mice with human-like bile acid composition, Nr1h4 deletion induces severe liver injury with elevated hepatic bile acid levels and increased serum markers of liver damage 5. Clinically, FXR agonists (obeticholic acid) serve as FDA-licensed add-on therapy for primary biliary cholangitis patients with inadequate response to ursodeoxycholic acid 6. Small heterodimer partner (SHP), a NR1H4 target gene, represents a potential therapeutic target for cholestatic diseases 5.