NEU4 is an exo-alpha-sialidase that catalyzes hydrolytic cleavage of terminal sialic acids from glycoconjugates, including gangliosides (GD1a, GM3, GD3) and glycoproteins 1. The enzyme exists in multiple forms with distinct subcellular localizations: the long form associates with the outer mitochondrial membrane, while the short form localizes to the endoplasmic reticulum and lysosomes 2. NEU4 can translocate between compartments and is secreted under certain conditions, allowing extracellular desialylation of cell surface glycoproteins 3. Mechanistically, NEU4 modulates diverse cellular processes through glycan remodeling. In kidney fibrosis, NEU4 interacts with Yes-associated protein (YAP) to promote its nuclear translocation and fibrotic gene activation 4. In ovarian carcinoma, the plasma membrane-localized NEU4 isoform 2 desialylates EGFR at the N196 residue, enhancing its hyperactivation and promoting peritoneal dissemination 5. Clinically, NEU4 expression is upregulated in renal fibrosis patients and correlates with worse survival in high-grade serous ovarian cancer 45. NEU4 shows therapeutic potential: a natural compound inhibitor (heptamethoxyflavone) attenuates kidney fibrosis in mice 4, and NEU4 expression in sialidosis and galactosialidosis patient cells clears lysosomal storage materials, suggesting gene therapy applications 1.