MFNG (Manic Fringe) is a glycosyltransferase that modifies O-linked fucose residues on EGF-like repeats of Notch receptors, thereby modulating Notch signaling activity 1. The protein plays a critical role in developmental processes, particularly in heart valve formation through endothelial-to-mesenchymal transition (EndMT). MFNG promotes EC migration and EndMT by enhancing Notch signaling pathway activity during atrioventricular canal and outflow tract development 1. During ventricular chamber development, temporal regulation of MFng expression controls sequential Notch ligand signaling: early MFng expression promotes Dll4-Notch1 signaling for trabeculation, while later downregulation permits Jag1/Jag2-mediated signaling for chamber maturation 2. Loss-of-function MFNG mutations impair EndMT and are associated with congenital heart valve defects, including tetralogy of Fallot-pulmonary valve stenosis 1. Beyond cardiac development, elevated MFNG expression correlates with poor prognosis in multiple cancers, including breast cancer, osteosarcoma, and renal carcinoma 345. In renal cell carcinoma, MFNG knockdown in endothelial cells reduces angiogenesis, cell viability, migration, and network formation 3. In triple-negative breast cancer, MFNG promotes cell growth and migration through Notch pathway activation, regulated by the GATA3/miR205-5p/MFNG feed-forward loop 5. These findings establish MFNG as both a developmental regulator and potential therapeutic target for congenital heart disease and cancer.