Secretin (SCT) is a gastrointestinal hormone synthesized by duodenal S cells that regulates acid-base homeostasis and energy metabolism 1. SCT exerts its biological effects by binding to secretin receptor (SCTR), a G-protein coupled receptor on cholangiocytes and other target cells. The hormone inhibits gastric acid secretion and stimulates pancreatic bicarbonate production, establishing the 'bicarbonate umbrella' that protects the small intestine from acid damage 2. Beyond pH regulation, SCT promotes diet-induced thermogenesis by activating brown adipocyte lipolysis, which signals satiation to the brain. SCT also regulates water homeostasis through hypothalamic-pituitary-renal mechanisms 1. In the central nervous system, SCT functions as a neuropeptide supporting hippocampal synaptic function and neural progenitor maintenance, with transcripts detected in brain tissue 1. Clinically, impaired SCT/SCTR signaling contributes to cholestatic liver diseases; secretin treatment restores cholangiocyte secretory processes and reduces ductular reaction, inflammation, and fibrosis in primary biliary cholangitis models 2. Conversely, prolonged secretin receptor antagonism ameliorates senescence and fibrosis in primary sclerosing cholangitis models by restoring FoxA2-mediated bile duct homeostasis 3. These findings position SCT as a pleiotropic hormone with therapeutic potential in metabolic and hepatobiliary disorders.