ADGRA3 (adhesion G protein-coupled receptor A3, formerly GPR125) is an orphan adhesion GPCR involved in multiple physiological processes 1. The receptor exhibits constitutive G protein-mediated signaling through Gi and Gs pathways, with a tethered agonist (stachel peptide) mechanism characteristic of adhesion GPCRs 2. ADGRA3 plays a central role in planar cell polarity signaling through disheveled recruitment 2. The receptor undergoes constitutive, clathrin-dependent endocytosis independent of β-arrestin, controlling surface expression and ligand accessibility 3. Functionally, ADGRA3 regulates adipose thermogenesis through constitutive Gs-PKA-CREB axis activation; hesperetin acts as a potential agonist inducing adipocyte browning and improving metabolic homeostasis 4. ADGRA3 is essential for reproductive tract development: knockout mice exhibit imperforate vagina in 44% of females through altered sex hormone responsiveness and apoptotic regulation 5, and obstructive azoospermia in 55% of males due to epididymal dysfunction and hormonal imbalance 6. In cancer, ADGRA3 expression correlates with reduced overall survival in uterine corpus endometrial carcinoma 7. A novel ADGRA3 variant has been identified in retinitis pigmentosa patients, suggesting potential sensory roles 8.