B4GALNT1 (beta-1,4-N-acetyl-galactosaminyltransferase 1) is a Golgi-localized glycosyltransferase that catalyzes the biosynthesis of gangliosides GM2, GD2, GT2, and GA2 from their precursors GM3, GD3, GT3, and GA3, respectively 1. The enzyme functions through dynamic membrane insertion of hydrophobic surface loops that enable substrate access within the lipid bilayer 2. In disease contexts, loss-of-function B4GALNT1 mutations cause hereditary spastic paraplegia type 26 (SPG26), characterized by progressive lower limb weakness, cognitive impairment, cerebellar ataxia, and peripheral neuropathy 3. Patient-derived mutations impair UDP-GalNAc binding and abolish ganglioside synthesis capacity 3. Additionally, CD38-mediated B4GALNT1 upregulation shifts T cell ganglioside profiles from GM3 to GM2, increasing intracellular calcium and suppressing IL-2 production in systemic lupus erythematosus 4. Conversely, B4GALNT1 overexpression promotes hepatocellular carcinoma (HCC) progression through multiple mechanisms: activating integrin α2β1/FAK/AKT signaling 5, reshaping the immunosuppressive microenvironment via HES4-SPP1-TAM/Th2 axis activation 6, enhancing PI3K-AKT-mTOR signaling 7, and promoting epithelial-mesenchymal transition 8. B4GALNT1 overexpression independently predicts poor HCC prognosis and represents a therapeutic target.