GPR68 is a proton-sensing G protein-coupled receptor that functions as a critical sensor of extracellular pH and mechanical stress 12. The receptor is nearly inactive at physiological pH 7.8 but becomes fully activated at acidic pH 6.8, with activation mediated by a network of titratable extracellular histidine residues rather than a single critical site 23. Upon proton binding, GPR68 undergoes conformational changes that trigger G protein coupling, primarily to Gq proteins, activating downstream phospholipase C signaling and generating inositol 1,4,5-trisphosphate and diacylglycerol 12. GPR68 also functions as a mechanosensor of fluid shear stress and membrane stretch in endothelial cells of small-diameter arteries, where it mediates flow-induced vascular dilation critical for cardiovascular physiology 1. Clinically, GPR68 mutations cause amelogenesis imperfecta, a hereditary enamel development disorder 4. In pathological contexts, GPR68 activation by tumor microenvironment acidification promotes glioblastoma survival through ATF4 suppression, making it a potential therapeutic target for inducing ferroptosis in cancer cells 5. Additionally, GPR68 expression increases in osteoarthritic cartilage where acidic conditions activate adaptive signaling responses affecting inflammation and matrix turnover 6.