The Glutamine-O-GlcNAc: A central metabolic-signaling crosstalk network in physiology and disease

Cells adapt to the environment through metabolic reprogramming, the core of which lies in the precise regulation of protein functions by converting nutritional status into functional signals. O-linked β-N-acetylglucosamine (O-GlcNAc) modification acts as a unique nutrient sensor, and its only precursor, uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), is synthesized via the hexosamine biosynthetic pathway (HBP). This pathway integrates the metabolic fluxes of glucose, amino acids (especially glutamine), fatty acids and nucleotides. By integrating current research, this paper systematically reviews how amino acid metabolism drives the dynamic levels of the HBP and O-GlcNAc, and further explores the complex competitive and synergistic crosstalk between O-GlcNAc modification and the phosphorylation and ubiquitination systems. The results demonstrate that O-GlcNAc determines protein stability by competing with or mutually regulating phosphorylation at the same or adjacent sites, as well as by modulating the activity of E3 ligases/deubiquitinases or interfering with the phosphorylation-ubiquitination cascade, thus forming a multidimensional “metabolism-signal-homeostasis” regulatory network. This metabolism-driven core regulatory network of O-GlcNAc constitutes the central mechanism for cellular environmental adaptation, and its dysregulation is a common feature of various diseases. Intervention strategies targeting key nodes of this network, especially combinatorial targeting, provide novel insights and potential targets for metabolic intervention in the treatment of related diseases.