Metabolic switch of glutamine-nitrogen regulates chromatin accessibility in hepatocellular carcinoma
Glutamine metabolic reprogramming sustains hepatocellular carcinoma (HCC) progression, yet how nitrogen flux is partitioned to support malignancy remains elusive. O-GlcNAcylation, a post-translational modification, can regulate enzyme activity and metabolic pathways, enabling tumor cells to rapidly adapt to external environmental changes. Here, we discover that O-GlcNAcylation of glutamate dehydrogenase 1 (GLUD1) reprograms glutamine nitrogen fate by diverting flux from ammonia production toward polyamine synthesis, thereby enhancing chromatin accessibility and progression in HCC. Mechanistically, O-GlcNAcylation at GLUD1 Ser517 obstructs the binding of the allosteric activator ADP binding at Arg516, consequently inhibiting its enzymatic activity. This suppression redirects glutamine-derived nitrogen to fuel polyamine biosynthesis, which in turn promotes epigenetic remodeling via increased chromatin accessibility (ATAC-seq) in oncogenic pathways and upregulation of atypical chemokine receptor 3 (ACKR3) (RNA-seq). Our work defines O-GlcNAcylation of GLUD1 signaling as a metabolic switch that coordinates nitrogen partitioning with epigenetic reprogramming to drive HCC progression, revealing a targetable axis for therapeutic intervention.