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However, the mechanism of aging\u2010related NAFLD remains unclear. Herein, we constructed an aging\u2010related hepatic steatosis model and analyzed the differentially expressed proteins (DEPs) in livers from young and old mice using liquid chromatography\u2013mass spectrometry. Five hundred and eighty\u2010eight aging\u2010related DEPs and novel pathways were identified. Aminoacyl tRNA synthetase complex\u2010interacting multifunctional protein 2 (AIMP2), the most significantly upregulated protein, promoted poly(ADP\u2010ribose) polymerase 1 (PARP1) activation in aging\u2010related hepatic steatosis. Additionally, mice liver\u2010specific O\u2010GlcNAcase knockout promoted AIMP2 and PARP1 expression. O\u2010GlcNAc transferase (OGT) overexpression and O\u2010GlcNAcase inhibition by genetic or pharmaceutical manipulations increased AIMP2 and PARP1 levels <jats:italic>in\u2009vitro<\/jats:italic>. Mechanistically, O\u2010GlcNAcylation increased AIMP2 protein stability, leading to its aggregation. Our study reveals O\u2010GlcNAcylated AIMP2 as a novel pathogenic regulator of aging\u2010related hepatic steatosis.<\/jats:p>","DOI":"10.1002\/1873-3468.14242","type":"journal-article","created":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T10:05:37Z","timestamp":1637748337000},"page":"128-145","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Comparative proteomic profiling reveals a pathogenic role\u00a0for the O\u2010GlcNAcylated AIMP2\u2013PARP1 complex in aging\u2010related hepatic steatosis in mice"],"prefix":"10.1002","volume":"596","author":[{"given":"Renlong","family":"Li","sequence":"first","affiliation":[{"name":"State key Laboratory of Cancer Biology National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases Air Force Military Medical University Xi'an 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