EDN3 (endothelin 3) is a vasoconstrictor peptide located on chromosome 20.2-q13.3 1 that functions as a key regulator in multiple physiological systems. Mechanistically, EDN3 signals through endothelin receptor type B (EDNRB) via cAMP-EPAC1-ERK activation pathways 2, modulating vascular tone, smooth muscle contraction, and systemic blood pressure regulation 3. Beyond cardiovascular function, EDN3 preserves β cell identity and metabolic function under hypoxic conditions by regulating genes involved in glucose sensing and β cell maturation 4, and promotes thermogenic differentiation of white adipose tissue, with EDNRB deletion impairing cold-induced browning and causing metabolic dysfunction 2. Clinically, EDN3 mutations are associated with Waardenburg syndrome 4B and Hirschsprung disease 4 56. These conditions reflect EDN3's critical role in neural crest cell migration and development. Additionally, EDN3 expression correlates with lung adenocarcinoma patient survival and serves as a potential prognostic biomarker 7. The gene's pleiotropic effects across vascular, metabolic, and developmental systems underscore its importance in normal physiology and disease pathogenesis, with emerging therapeutic potential in metabolic disorders, diabetes, and cancer.