GPR31 is a metabolite-sensing G protein-coupled receptor located on chromosome 6 1 that functions as a proton sensor and bioactive lipid receptor with broad physiological significance. Mechanistically, GPR31 is activated by multiple ligands including 12-hydroxyeicosatetraenoic acid (12-HETE), an arachidonic acid metabolite 2, and pyruvate 3. Upon activation, GPR31 signals through Gαi3-dependent mechanisms involving PKCδ-MAPK and p38 MAPK pathways 45. GPR31 plays critical roles in multiple diseases. In hepatic ischemia-reperfusion injury, the ALOX12-12-HETE-GPR31 axis mediates inflammatory responses and liver damage; blocking this pathway protects against dysfunction in mice, pigs, and nonhuman primates 2. In metabolic dysfunction-associated steatohepatitis (MASH), GPR31 promotes hepatic lipotoxicity and fibrosis through Gαi3-PKCδ-MAPK signaling; GPR31 inhibition or hepatocyte-specific deficiency blocks disease progression 4. In bone homeostasis, the Alox12/12-HETE/GPR31 axis regulates osteoclast differentiation and osteoporosis development 5. Conversely, in the intestinal immune system, GPR31 activation on dendritic cells by pyruvate promotes beneficial transepithelial dendrite formation, enhancing antigen sampling 3. Clinically, GPR31 represents a druggable therapeutic target. The small-molecule inhibitor G4451 effectively blocks MASH progression in rodents and primates 4, while GPR31 inhibition also restores CAR-T cell function in ovarian cancer models 6.