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Although insulin resistance (IR) plays a central role in metabolic diseases, in the liver, insulin- or substrate-driven &lt;i&gt;de novo&lt;\/i&gt; lipogenesis (DNL) promotes triglyceride accumulation through multiple complex regulatory mechanisms, including specific transcription factors, regardless of whether IR is primary or not. Elevated free fatty acids, resulting from increased adipose lipolysis, further augment hepatic lipid storage and contribute to IR and the progression of MASLD through lipotoxic intermediates such as diacylglycerols and ceramides, as well as other pathways. Numerous studies have identified DNL as a major, yet modifiable, contributor to MASLD. In addition, zonal differences in hepatic insulin signaling, non-classical insulin signaling pathways, and activation of the mechanistic target of rapamycin complex 1 and protein kinase C pathways appear to be involved in the development of selective hepatic IR. Recently, new pharmacologic agents, including resmetirom, have shown promise in improving steatohepatitis and fibrosis in MASLD. Nevertheless, sustained weight loss through lifestyle modification remains the cornerstone of MASLD prevention and therapy. Further mechanistic understanding of how IR and substrate overload promote DNL and hepatic fat accumulation is critical for developing effective treatments for MASLD.<\/jats:p>","DOI":"10.4093\/dmj.2025.0644","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:17:39Z","timestamp":1756945059000},"page":"964-986","update-policy":"https:\/\/doi.org\/10.4093\/crossmark_policy","source":"Crossref","is-referenced-by-count":87,"title":["Hepatic Insulin Resistance and Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease: New Insights into Mechanisms and Clinical Implications"],"prefix":"10.4093","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4489-9754","authenticated-orcid":true,"given":"Xuan Trong","family":"Truong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8832-3052","authenticated-orcid":true,"given":"Dae 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