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Defects in autophagy contribute to the development of MASLD; however, the role of Unc-51\u2013like autophagy-activating kinase 1 (ULK1) in the pathophysiology of MASLD remains unclear. Herein, we show that ULK1, a serine\/threonine kinase and core autophagy protein, is significantly repressed in human MASH livers, and that hepatocyte-specific loss of ULK1 promotes, unexpectedly, hepatic steatosis and progression to liver fibrosis, without affecting basal autophagy flux. Phospho-proteomics identified the transcriptional coactivator NCOA3 as a downstream phospho-target of ULK1. Mechanistically, ULK1 phosphorylates NCOA3 to repress its transcriptional activity and restrain the CREB\/CBP-mediated de novo lipogenic program. Accordingly, a phosphorylation-deficient NCOA3 mutant drives CREB\/CBP-mediated lipogenesis, whereas genetic or pharmacological NCOA3 inhibition prevents steatosis, hepatic inflammation, and profibrotic signaling. Hence, ULK1-mediated NCOA3 phosphorylation is a fundamental and druggable checkpoint against the entire MASLD spectrum.<\/jats:p>","DOI":"10.1172\/jci191101","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T16:00:43Z","timestamp":1775145643000},"source":"Crossref","is-referenced-by-count":1,"title":["The ULK1-NCOA3 axis restrains de novo lipogenesis and prevents diet-induced steatohepatitis and fibrosis in mice"],"prefix":"10.1172","volume":"136","author":[{"given":"Young Do","family":"Koo","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, David Geffen School of Medicine and UCLA Health, UCLA, Los Angeles, California, USA."},{"name":"Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. 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