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The <jats:italic>O<\/jats:italic>\u2010GlcNAcylation cycle is precisely controlled by collaboration between <jats:italic>O<\/jats:italic>\u2010GlcNAc transferase and <jats:italic>O<\/jats:italic>\u2010GlcNAcase. Uridine\u2010diphosphate\u2010<jats:italic>N<\/jats:italic>\u2010acetylglucosamine, the sole donor of <jats:italic>O<\/jats:italic>\u2010GlcNAcylation 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 <jats:italic>O<\/jats:italic>\u2010GlcNAcylation a pivotal nutrient sensor for the metabolism of carbohydrates, amino acids, lipids and nucleotides. <jats:italic>O<\/jats:italic>\u2010GlcNAcylation, 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 <jats:italic>O<\/jats:italic>\u2010GlcNAcylation also plays a specific pathological role in these processes. Therefore, this review describes the unique features of <jats:italic>O<\/jats:italic>\u2010GlcNAcylation and its dynamic homeostasis maintenance. Additionally, it explains the underlying nutritional sensitivity of <jats:italic>O<\/jats:italic>\u2010GlcNAcylation 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 <jats:italic>O<\/jats:italic>\u2010GlcNAcylation in nonalcoholic fatty liver disease, nonalcoholic steatohepatitis and hepatic fibrosis, and focuses on the adverse effects of hyper <jats:italic>O<\/jats:italic>\u2010GlcNAcylation on liver cancer progression and metabolic reprogramming.<\/jats:p>","DOI":"10.1111\/liv.15812","type":"journal-article","created":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T08:57:20Z","timestamp":1702976240000},"page":"293-315","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Protein <i>O<\/i>\u2010GlcNAcylation: The sweet hub in liver metabolic flexibility from a (patho)physiological perspective"],"prefix":"10.1111","volume":"44","author":[{"given":"Ya\u2010Jie","family":"Hu","sequence":"first","affiliation":[{"name":"Key Laboratory of Bovine Disease Control in Northeast China of Ministry of Agriculture and Rural 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