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Treatments for fibrosis remain experimental, in part because no unifying mechanism has been identified that initiates liver fibrosis. Necroptosis has been implicated in multiple liver diseases. Here, we report that O-linked \u03b2-N-acetylglucosamine (O-GlcNAc) modification protects against hepatocyte necroptosis and initiation of liver fibrosis. Decreased O-GlcNAc levels were seen in patients with alcoholic liver cirrhosis and in mice with ethanol-induced liver injury. Liver-specific O-GlcNAc transferase\u2013KO (OGT-LKO) mice exhibited hepatomegaly and ballooning degeneration at an early age and progressed to liver fibrosis and portal inflammation by 10 weeks of age. OGT-deficient hepatocytes underwent excessive necroptosis and exhibited elevated protein expression levels of receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), which are key mediators of necroptosis. Furthermore, glycosylation of RIPK3 by OGT is associated with reduced RIPK3 protein stability. Taken together, these findings identify OGT as a key suppressor of hepatocyte necroptosis, and OGT-LKO mice may serve as an effective spontaneous genetic model of liver fibrosis.<\/jats:p>","DOI":"10.1172\/jci.insight.127709","type":"journal-article","created":{"date-parts":[[2019,10,31]],"date-time":"2019-10-31T11:01:33Z","timestamp":1572519693000},"source":"Crossref","is-referenced-by-count":89,"title":["O-GlcNAc transferase suppresses necroptosis and liver fibrosis"],"prefix":"10.1172","volume":"4","author":[{"given":"Bichen","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Physiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3650-1507","authenticated-orcid":true,"given":"Min-Dian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Physiology 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