The O-GlcNAc modification is a nutrient rheostat that transiently regulates functions, localization, and stability of proteins in response to fluctuations in nutrient intake. Indeed, the nucleotide sugar donor for this modification, UDP-GlcNAc, is the final product of the Hexosamine Biosynthetic Pathway (HBP). This pathway integrates carbohydrate, amino acid, nucleotide, and fatty acid metabolisms to maintain a suitable pool of UDP-GlcNAc. UDP-GlcNAc is then used for glycan synthesis, including O-GlcNAcylation catalyzed by the O-GlcNAc Transferase (OGT). On the other hand, the O-GlcNAcase (OGA) dynamically hydrolyzes O-GlcNAc, releasing the protein's modification.