GPR65 is a proton-sensing G protein-coupled receptor that functions as a cellular pH sensor, activated optimally at pH 7.4 to monitor extracellular acidification and generate adaptive responses 1. The receptor primarily couples to Gs proteins, activating adenylyl cyclase and increasing cAMP levels through a network of titratable histidine and carboxylic acid residues extending from the extracellular surface to transmembrane regions 1 2. GPR65 plays critical roles in immune regulation and inflammatory responses, particularly in acidic tissue environments. In hepatic macrophages, GPR65 promotes liver fibrosis by activating Gαq-Ca²⁺-JNK/NF-κB pathways, leading to increased TNF-α, IL-6, and TGF-β production 3. In cancer, GPR65 on tumor-associated macrophages senses tumor-derived lactate, triggering HMGB1 release via cAMP/PKA/CREB signaling to promote glioma progression 4. The receptor also drives tumor growth in obesity-associated cancers by responding to oleic acid-induced acidification 5. Additionally, GPR65-expressing vagal sensory neurons detect nutrients in the gastrointestinal tract, contributing to gut-brain communication 6. These diverse functions position GPR65 as a key regulator linking pH sensing to immune responses, metabolism, and disease pathogenesis.