The therapeutic potential of orphan adhesion G-protein-coupled receptors

# The therapeutic potential of orphan adhesion G-protein-coupled receptors *Published: 2026 Feb 26* Adhesion G-protein-coupled receptors (aGPCRs) are essential membrane proteins that contribute to diverse human pathologies, including cancer, psychiatric disorders and autoimmune diseases. A defining feature of these receptors is the large N terminus including the GPCR autoproteolysis-inducing domain, which mediates autoproteolysis and enables complex modes of activation through both cis and trans signalling. Recent breakthroughs in structural biology, in particular, cryogenic electron microscopy structures of aGPCRs, have transformed our understanding of receptor activation and facilitated development of small-molecule agonists and antibody-based strategies, which hold considerable promise for therapeutic intervention. In this Review, we summarize the roles of aGPCRs in human disease and in phenotypes characterized in animal models. We consolidate current insights into aGPCR structure-function relationships, highlight how distinct activation mechanisms are already being harnessed to modulate receptor activity in vitro and in vivo, and discuss how these principles could be leveraged for future therapeutic targeting. DOI: 10.1038/s41573-025-01371-6