GPR25 is a G protein-coupled receptor that functions as the primary receptor for the C-X-C chemokine CXCL17, mediating lymphocyte homing to non-intestinal mucosal tissues and the central nervous system 1. Upon CXCL17 binding, GPR25 undergoes conformational changes that activate downstream signaling through G proteins, particularly the RhoA pathway, which regulates cytoskeletal dynamics and integrin activity 1. This signaling axis directs lymphocyte recruitment to barrier epithelia of the respiratory tract, upper gastrointestinal tract, biliary system, and genitourinary tracts 1. GPR25 is preferentially expressed on innate lymphocytes, activated B and T cells, tissue resident memory cells, and regulatory T cells in non-intestinal mucosal tissues 1. The GPR25-CXCL17 axis also functions in CNS immune regulation, with GPR25 expressed on cerebrospinal fluid T cells and CXCL17 produced by neurons 1. Notably, GPR25 orthologs are conserved across vertebrates, with fish GPR25 receptors responding to human CXCL17, indicating ancient evolutionary origin of this ligand-receptor pair 23. Genome-wide association studies suggest GPR25 provides protection against autoimmunity 1. GPR25 was originally discovered as an orphan GPCR on chromosome 1.1 4.