INSL5 (insulin-like peptide 5) is a hormone primarily produced by enteroendocrine L-cells in the colon that functions as the endogenous ligand for the G-protein coupled receptor RXFP4 12. The protein adopts an insulin-like structure with characteristic A and B chains connected by disulfide bonds and activates RXFP4 with high potency while showing no activity on RXFP3 1. INSL5 serves as a specific marker for enteroendocrine cells in the large intestine, where it may function in an autocrine/paracrine signaling system with RXFP4 expressed on colonocytes 2. Current evidence suggests INSL5-RXFP4 acts as a protective energy sensor, potentially linking energy availability, homeostasis, and inflammation through regulation of immune responses and signaling via vagal sensory neurons 3. In cancer contexts, INSL5 shows altered expression patterns - it is decreased in colorectal cancer tissues where high expression correlates with better prognosis 4, while elevated INSL5 in nasopharyngeal carcinoma promotes tumor progression through STAT5 activation and enhanced glycolysis 5. The peptide can be detected in tissue extracts and cell culture supernatants using mass spectrometry methods 6.