POFUT1 catalyzes O-fucosylation of conserved serine and threonine residues within epidermal growth factor (EGF) domains, using GDP-fucose as the donor substrate and requiring proper disulfide pairing in target EGF domains. This modification is essential for NOTCH signaling, where initial fucosylation by POFUT1 creates a substrate for FRINGE enzymes to extend the glycan, which is required for optimal ligand binding and canonical NOTCH signaling induced by DLL1 or JAGGED1. POFUT1 also fucosylates AGRN and regulates its ability to cluster acetylcholine receptors. At the tissue level, endothelial POFUT1 controls injury-induced liver fibrosis by repressing fibrinogen synthesis; loss of POFUT1 in liver sinusoidal endothelial cells promotes LSEC capillarization and hepatic stellate cell activation, exacerbating fibrosis through paracrine fibrinogen signaling 1. In placental trophoblasts, POFUT1 promotes angiogenesis through O-fucosylation of uPA, facilitating uPA-uPAR binding and RhoA pathway activation 2. Dysregulation of POFUT1 is implicated in multiple diseases. Haploinsufficiency causes Dowling-Degos disease, a rare autosomal dominant genodermatosis characterized by acquired reticulate hyperpigmentation, follicular papules, and perioral scars 3. Biallelic loss-of-function variants cause severe developmental delay, microcephaly, cardiac and vascular defects 4. Conversely, POFUT1 overexpression, driven by copy number variations and epigenetic alterations, promotes tumorigenesis in colorectal, gastric, lung, hepatocellular, and esophageal squamous cell carcinomas by activating Notch, Wnt/β-catenin, and PI3K/AKT/mTOR pathways, enhancing cell proliferation and migration while suppressing apoptosis 5. POFUT1 overexpression is detectable early in tumor development and in patient sera, and the POFUT1/Notch axis represents a promising therapeutic target in cancer 6.