B3GALT4 (beta-1,3-galactosyltransferase 4) is a Golgi-localized glycosyltransferase that catalyzes the transfer of galactose in glycosphingolipid biosynthesis, serving as the primary GM1 ganglioside synthase 1. Beyond its characterized role in ganglioside synthesis, B3GALT4 additionally functions in transferring galactose to glycosylphosphatidylinositol (GPI)-anchored protein side-chains, demonstrating functional cross-talk between GPI and glycosphingolipid biosynthetic pathways 2. In disease contexts, B3GALT4 dysregulation associates with multiple pathologies. Substantia nigra neurons in Parkinson's disease show significantly decreased B3GALT4 gene expression, correlating with reduced GM1 and other brain gangliosides 3. Experimental knockdown of B3GALT4 reduces GM1 levels and dramatically increases dopaminergic neurodegeneration vulnerability to neurotoxins 1, suggesting B3GALT4-mediated ganglioside synthesis protects against neuronal stress. In colorectal cancer, elevated B3GALT4 expression independently predicts poor overall survival and correlates with B7-H3 expression, with combined high expression conferring worst prognosis 4. B3GALT4 also emerges as a dysregulated therapeutic target in phospholipid/sphingolipid metabolism pathways driving colorectal cancer progression 5. Additionally, B3GALT4 DNA hypomethylation associates with late-onset Alzheimer's disease 6, and altered methylation correlates with aggressive neuroblastoma phenotypes 7.