Protein O‐GlcNAcylation: The sweet hub in liver metabolic flexibility from a (patho)physiological perspective

O-GlcNAcylation is a dynamic, reversible and atypical O-glycosylation that regulates various cellular physiological processes via conformation, stabilisation, localisation, chaperone interaction or activity of target proteins. The O-GlcNAcylation cycle is precisely controlled by collaboration between O-GlcNAc transferase and O-GlcNAcase. Uridine-diphosphate-N-acetylglucosamine, the sole donor of O-GlcNAcylation produced by the hexosamine biosynthesis pathway, is controlled by the input of glucose, glutamine, acetyl coenzyme A and uridine triphosphate, making it a sensor of the fluctuation of molecules, making O-GlcNAcylation a pivotal nutrient sensor for the metabolism of carbohydrates, amino acids, lipids and nucleotides. O-GlcNAcylation, particularly prevalent in liver, is the core hub for controlling systemic glucose homeostasis due to its nutritional sensitivity and precise spatiotemporal regulation of insulin signal transduction. The pathology of various liver diseases has highlighted hepatic metabolic disorder and dysfunction, and abnormal O-GlcNAcylation also plays a specific pathological role in these processes. Therefore, this review describes the unique features of O-GlcNAcylation and its dynamic homeostasis maintenance. Additionally, it explains the underlying nutritional sensitivity of O-GlcNAcylation and discusses its mechanism of spatiotemporal modulation of insulin signal transduction and liver metabolic homeostasis during the fasting and feeding cycle. This review emphasises the pathophysiological implications of O-GlcNAcylation in nonalcoholic fatty liver disease, nonalcoholic steatohepatitis and hepatic fibrosis, and focuses on the adverse effects of hyper O-GlcNAcylation on liver cancer progression and metabolic reprogramming.