ADGRG3 (GPR97) is an adhesion G protein-coupled receptor that functions through a tethered peptide agonist mechanism rather than glucocorticoid binding as previously proposed 1. The receptor is activated when mechanical shear forces cause dissociation of its N-terminal and C-terminal fragments, exposing a tethered agonist that binds to stabilize the active state 1. ADGRG3 couples promiscuously to multiple G proteins including G13, Gs, and Gi, mediating diverse downstream signaling pathways 1. The receptor is highly expressed in neutrophils and granulocytes, where it plays crucial roles in antimicrobial defense 23. Upon activation, ADGRG3 stimulates neutrophil polarization, migration, and reactive oxygen species production while enhancing bacterial uptake and killing 21. The receptor functions through a macromolecular complex involving CD177, membrane proteinase 3 (mPR3), PAR2, and CD16b, which collectively triggers inflammatory processes and endothelial activation 3. ADGRG3 expression is upregulated during systemic inflammation and on disease-associated neutrophils 23. In cancer contexts, particularly uterine corpus endometrial carcinoma, elevated ADGRG3 expression correlates with poor patient outcomes and immune cell infiltration 4. The receptor represents a potential therapeutic target for neutrophil-mediated inflammatory diseases and certain cancers.