CCDC80 (coiled-coil domain containing 80) is a secreted protein that functions as a key regulator of cellular adhesion, matrix organization, and tissue homeostasis. The protein promotes cell adhesion and extracellular matrix assembly, with particular importance in maintaining vascular smooth muscle cell contractile phenotype 1. CCDC80 mechanistically interacts with JAK2 kinase, inhibiting JAK2/STAT3 signaling pathway activation, which regulates cell proliferation, migration, and phenotypic switching 12. In cardiovascular contexts, CCDC80 deficiency leads to adverse vascular remodeling and increased susceptibility to aortic dissection through loss of smooth muscle cell contractile phenotype 1. Exercise induces secretion of a C-terminal CCDC80 fragment (CCDC80tide) that provides cardioprotection against pathological cardiac remodeling 2. CCDC80 exhibits context-dependent roles in cancer, acting as a tumor suppressor in the stromal microenvironment while being associated with metastasis and chemoresistance when expressed in cancer cells 345. The protein also functions as an adipokine, with altered expression in obesity linked to metabolic dysfunction and inflammation 6. Clinically, CCDC80 represents a potential therapeutic target for cardiovascular diseases, cancer treatment, and metabolic disorders 147.