ADGRG5 (GPR114) is an orphan adhesion G protein-coupled receptor that functions as a Gs-coupled receptor mediating adenylate cyclase activation 1. Like other adhesion GPCRs, ADGRG5 undergoes autoproteolytic cleavage during biosynthesis, generating an extracellular domain and a 7-transmembrane domain that remain non-covalently associated in a low-activity state 2. Ligand binding or extracellular domain dissociation reveals a tethered agonist peptide that activates downstream G protein signaling 23. ADGRG5 is expressed in immune cells including monocytes, macrophages, and lymphocytes, where it may regulate immune cell function 4. In cancer biology, ADGRG5 expression is elevated in uterine corpus endometrial carcinoma and cervical squamous cell carcinoma, correlating with worse survival outcomes and serving as a potential immunotherapeutic target 56. Small-molecule antagonists and partial agonists have been identified that modulate ADGRG5 activity, offering therapeutic potential 23. Additionally, genetic variants in ADGRG5 may influence the penetrance of Leber's hereditary optic neuropathy 7. As an underexplored aGPCR target, ADGRG5 represents a promising avenue for therapeutic intervention in various diseases including cancer and neurological disorders 8.