GPR21 is a class-A orphan G protein-coupled receptor with constitutive basal activity that couples to multiple G proteins, including Gq and Gs family members 12. Structurally, an agonist-like motif in extracellular loop 2 occupies the orthosteric pocket to promote activation, with a putative side pocket representing an alternative ligand binding site 1. Phylogenetic analysis suggests GPR21 may associate with fatty acids as potential ligands 3. GPR21 is highly expressed in macrophages and hypothalamus, where it regulates immune cell migration and inflammatory responses 4. In obesity-induced insulin resistance, GPR21 deletion improves glucose tolerance and insulin sensitivity by reducing proinflammatory macrophage infiltration into adipose tissue and liver 45. Pharmacological GPR21 inhibition reduces TNF-α and IL-1β release from M1 macrophages while modulating M2 migration 2. Clinically, GPR21 expression is elevated in peripheral blood mononuclear cells of type 2 diabetes patients, correlating with HbA1c and fasting glucose levels 5. GPR21 expression is downregulated in multiple cancer tissues (cervical, breast, skin, prostate, astrocytoma), suggesting potential diagnostic utility 6. GPR21 inhibitors represent an experimental therapeutic approach for type 2 diabetes and metabolic syndrome 78.