ST3GAL5 (ST3 beta-galactoside alpha-2,3-sialyltransferase 5) is a Golgi-resident sialyltransferase that catalyzes the transfer of sialyl groups from CMP-NeuAc to the non-reducing terminal galactose of glycosphingolipids, primarily synthesizing ganglioside GM3 1. The enzyme can also accept alternative substrates including D-galactosylceramide and asialo-GM1/GM2, though with lower efficiency [UniProt annotation]. ST3GAL5-synthesized gangliosides regulate multiple cellular processes including proliferation, differentiation, and apoptosis through lipid raft organization and receptor signaling modulation 2. Pathologically, ST3GAL5 dysfunction causes GM3 synthase deficiency, manifesting as salt and pepper developmental regression syndrome characterized by intellectual disability, epilepsy, microcephaly, hearing loss, and pigmentation abnormalities 34. Beyond monogenic disease, reduced ST3GAL5 expression correlates with better survival in colorectal cancer, while GM3 deficiency promotes ferroptosis in vascular smooth muscle cells and exacerbates abdominal aortic aneurysm development 5. Additionally, ST3GAL5-mediated sialylation of neutrophil glycoproteins like CD177 restricts neuroinflammation following CNS injury, and valproic acid—an FDA-approved ST3GAL5 upregulator—attenuates neuroinflammatory responses 6. These findings position ST3GAL5 as a pleiotropic enzyme with roles in developmental disease, vascular pathology, cancer progression, and neuroimmunity.