RXFP1 is a G protein-coupled receptor that mediates relaxin signaling through adenylate cyclase activation and cAMP elevation 1. The receptor signals through a unique autoinhibition mechanism distinct from classical GPCRs 2, activating multiple pathways including JAK3-STAT3 and tyrosine kinase cascades that inhibit phosphodiesterase 3. RXFP1 has tissue-specific expression with important roles in reproductive physiology, fetoplacental growth, and cardiovascular homeostasis 45. In disease contexts, RXFP1 dysfunction contributes to fibrotic pathology through reduced expression in lung and skin tissues, potentially explaining treatment resistance to relaxin therapy 1. RXFP1 activation promotes cancer cell survival through anti-apoptotic signaling, angiogenesis, and chemoresistance 6. RXFP1 expression and function show striking species differences between rodents and humans, creating translational challenges 7. Clinical applications include heart failure and fibrotic disease treatment, though early trials in systemic sclerosis failed 1. Alternative splicing and receptor dimerization regulate signaling 1, and engineered relaxin-2 fusion proteins with extended half-lives show promise for therapeutic development 8.