GPR26 is a brain-enriched orphan G protein-coupled receptor that functions as a constitutively active cAMP-elevating receptor 1. It couples to Gs-alpha proteins to stimulate adenylate cyclase and increase intracellular cAMP 2, with constitutive activity regulated by ubiquitin-dependent K286 degradation 3. GPR26 serves as a central regulator of energy homeostasis; GPR26 deficiency causes hyperphagia, hypometabolism, and early-onset obesity through increased hypothalamic AMPK activation 4. In cancer biology, GPR26 is epigenetically silenced in glioblastomas through CpG island methylation on chromosome 10.3-26.1, and its restoration increases cAMP to promote astrocytic differentiation 5. GPR26 demonstrates antitumor activity in hepatocellular carcinoma when highly expressed 3. In diabetes, GPR26 is initially upregulated in monocytes under hyperglycemia to counteract inflammatory activation, ROS production, and monocyte adhesion; however, GPR26 is chr10 suppressed in type 2 diabetic patients, correlating inversely with BMI and HbA1c 6. These findings position GPR26 as a potential therapeutic target for metabolic, oncologic, and inflammatory disorders 78.