GPR31 is a proton-sensing G protein-coupled receptor that binds arachidonate metabolites, particularly 12-hydroxyeicosatetraenoic acid (12-HETE), and regulates inflammatory and metabolic responses. The receptor signals through Gαi3 and downstream kinase cascades including p38 MAPK and PKCδ-MAPK pathways to modulate cellular activation and lipid metabolism. GPR31 functions as a metabolite sensor in multiple tissues. In the intestine, GPR31 on type 1 dendritic cells is activated by the bacterial metabolite pyruvate, promoting transepithelial dendrite formation and antigen uptake 1. In bone, the ALOX12/12-HETE/GPR31 signaling axis regulates osteoclast differentiation and bone homeostasis 2. Clinically, GPR31 emerges as a druggable target in multiple disease contexts. In hepatic ischemia-reperfusion injury, 12-HETE binding to GPR31 triggers inflammation and cell death; blocking 12-HETE production prevents liver dysfunction in mice, pigs, and nonhuman primates 3. In metabolic dysfunction-associated steatohepatitis (MASH), GPR31 drives hepatic lipotoxicity and fibrosis through Gαi3-dependent mechanisms; the small-molecule inhibitor G4451, which blocks the GPR31-Gαi3 interaction, effectively prevented MASH progression in rodents and nonhuman primates 4. In diabetic retinopathy, elevated 12-HETE levels activate GPR31 on retinal endothelial cells, promoting inflammation via p38 MAPK and endothelial dysfunction 5. Recent work also demonstrates that inhibiting 12-HETE/GPR31 signaling restores CAR-T cell function in ovarian cancer by reducing lipid peroxidation-driven exhaustion.