Sphingosine-1-phosphate receptor 3 (S1PR3) is a member of the G protein-coupled receptor (GPCR) family, structurally characterized by seven transmembrane domains. It exhibits diverse biological functions by binding to three major Gα protein subtypes (Gi/o, Gq, and G12/13), thereby activating downstream signaling pathways such as phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), phospholipase C/calcium (PLC/Ca²⁺), and Ras homolog family member A/Rho-associated coiled-coil containing protein kinase (RhoA/ROCK). S1PR3 displays tissue- and cell-specific expression patterns, with high levels observed in the cardiovascular system (endothelial cells, vascular smooth muscle cells, cardiac fibroblasts), immune system (macrophages, dendritic cells), nervous system (astrocytes, microglia), and liver (hepatocytes, hepatic stellate cells). This expression profile enables S1PR3 to play pivotal roles in regulating inflammation, maintaining vascular homeostasis, repairing liver damage, protecting neural function, and preserving immune balance. Under pathological conditions, S1PR3 exhibits dual functionality. At physiological concentrations or under mild pathological conditions, it exerts protective effects—for instance, preventing cardiomyocyte and hepatocyte apoptosis and maintaining blood-brain barrier (BBB) integrity. Conversely, overactivation leads to tissue damage, including exacerbated inflammatory infiltration (e.g., in acute respiratory distress syndrome, ARDS), promotion of fibrosis (e.g., hepatic fibrosis), and vascular injury (e.g., atherosclerosis). S1PR3 has emerged as a promising therapeutic target for cardiovascular diseases, neurological injuries, and liver disorders. However, clinical application of S1PR3 modulators is hindered by off-target effects (e.g., bradycardia due to insufficient subtype selectivity) and risks of immunosuppression, underscoring the need for more selective ligands and personalized therapeutic regimens.