NEU3 at the Plasma Membrane: Context-Dependent Ganglioside Remodeling in Health and Disease

Cell-surface gangliosides tune receptor signaling, cell-state transitions, and responses to stress. NEU3 is a mammalian sialidase associated with the plasma membrane and endomembranes that preferentially removes terminal sialic acids from gangliosides. Here, we critically review biochemical studies, cultured-cell experiments, animal models, and observations in human tissues that link NEU3 to myogenesis, hypoxic adaptation, cardioprotection, ganglioside storage disorders, cancer, fibrosis, and intestinal inflammation. Across these settings, NEU3 can alter the local ganglioside environment of receptors and signaling complexes, but the strength and direction of the resulting effects vary with cell type, substrate availability, localization, expression level, and duration of activity. We therefore frame NEU3 as a context-dependent regulator rather than a uniformly beneficial or harmful enzyme. This evidence-weighted model helps reconcile apparently opposing findings while highlighting important uncertainties in membrane topology, extracellular delivery, substrate selection, and pharmacological specificity. Selective inhibitors, tissue-restricted delivery, and biomarker-guided approaches are promising, but clinical translation will require stronger target-engagement data and broader in vivo validation.