MRGPRX4 is a G protein-coupled receptor (GPCR) expressed in sensory neurons of the dorsal root ganglion that serves as a primary mediator of bile acid-induced itch 1. The receptor is activated by bile acids, including deoxycholate, chenodeoxycholate, and taurocholate, with a particular preference for 3-sulfated bile acid variants that accumulate in cholestatic patients experiencing itch symptoms 2. Upon bile acid binding, MRGPRX4 undergoes conformational change and couples to Gq/G11 proteins, activating phospholipase C-beta to generate second messengers—inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG)—that mobilize intracellular calcium and modulate downstream signaling 3. Beyond bile acids, MRGPRX4 also responds to phosphate-modified drugs, explaining treatment-limiting pruritus associated with phosphorylated medications 4. Clinically, elevated plasma bile acids show positive correlation with cholestatic itch severity, establishing MRGPRX4 as a validated therapeutic target 1. Novel therapeutic strategies include bile acid derivatives lacking the 3-hydroxyl group that reduce hepatic injury without inducing itch 2, and MRGPRX4 antagonists represent emerging approaches for managing pruritus in liver diseases 5. This receptor-ligand system represents a mechanistic breakthrough in understanding and treating cholestasis-associated itch.