RXFP4 is a G protein-coupled receptor (GPCR) that functions as a high-affinity receptor for insulin-like peptide 5 (INSL5) and also recognizes relaxin-3, bradykinin, and kallidin 1. The receptor couples to Gi proteins via a pertussis toxin-sensitive mechanism to inhibit cAMP accumulation 1. Structurally, RXFP4 shares conserved transmembrane domain residues with RXFP3 that enable relaxin-3 binding, while INSL5's distinct C-terminal residue composition ensures RXFP4 selectivity 2. RXFP4 is predominantly expressed in gastrointestinal enterochromaffin cells that produce serotonin, where it regulates serotonin production and release through cAMP-dependent mechanisms and TPH1 expression 3. The INSL5-RXFP4 system functions as a protective energy sensor, linking energy availability and homeostasis to immune regulation and inflammation control 4. RXFP4 is expressed throughout immune organs, particularly in splenic dendritic cells, where INSL5 signaling reduces proinflammatory cytokines (IL-1β, IL-6, TNFα) and modulates immune cell development 5. RXFP4 also signals through vagal sensory neurons to the central nervous system and exhibits autocrine/paracrine functions within intestinal and immune tissues 4. Selective RXFP4 agonists have been developed as potential therapeutic agents for metabolic and immunological disorders 6.