POFUT1 is a protein O-fucosyltransferase that catalyzes O-linked fucosylation of serine and threonine residues within EGF domains using GDP-fucose as substrate 1. This modification is essential for NOTCH signaling, where initial POFUT1-mediated fucosylation primes substrates for FRINGE-catalyzed extension, enabling optimal ligand binding and canonical NOTCH activation by DLL1 or JAGGED1 2. POFUT1 also fucosylates AGRN to regulate acetylcholine receptor clustering. Dysregulation of POFUT1 underlies multiple diseases: loss-of-function mutations cause Dowling-Degos disease (characterized by hyperpigmentation and follicular papules) and developmental disorders with microcephaly and cardiac defects 34. Conversely, POFUT1 overexpression, driven by copy number variations and epigenetic alterations, promotes tumorigenesis across colorectal, gastric, lung, hepatocellular, and esophageal cancers by hyperactivating NOTCH, Wnt/β-catenin, and PI3K/AKT/mTOR pathways to enhance proliferation, migration, and EMT while suppressing apoptosis 56. In liver endothelial cells, POFUT1 deletion increases fibrinogen expression through enhanced NOTCH/HES1/STAT3 signaling, exacerbating hepatic fibrosis 7. POFUT1 overexpression is detectable in early-stage tumors and patient sera, positioning it as a promising biomarker and therapeutic target 5.