NEU3 is a plasma membrane-associated exo-alpha-sialidase that catalyzes hydrolytic cleavage of terminal sialic acid residues from gangliosides and glycoconjugates 1. It displays high catalytic efficiency for gangliosides including GM3, GD1a, and GD3, and is anchored to membranes through S-acylation rather than traditional transmembrane domains 2. NEU3 regulates transmembrane signaling by modulating ganglioside content and directly interacting with signaling receptors; it desialylates EGFR to activate downstream proliferation signaling 3. Additionally, NEU3 contributes to clathrin-mediated endocytosis and receptor trafficking to early and recycling endosomes 4. Pathologically, NEU3 upregulation is implicated in cancer progression through desialylation of gangliosides like GM3, which normally inhibits EGFR activation 5. In rheumatoid arthritis, EPO-induced NEU3 expression via JAK2/STAT5 signaling promotes fibroblast-like synoviocyte migration and invasion 6. NEU3 is similarly upregulated in pulmonary fibrosis, where it appears both necessary and sufficient for disease progression through positive feedback loops with profibrotic cytokines 7. Notably, intestinal HIF-2α activation during obesity increases NEU3 expression to promote ceramide metabolism, contributing to hepatic steatosis 8. NEU3 inhibitors represent promising therapeutic targets for fibrosis and potentially other NEU3-driven pathologies.