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We sought to identify endogenous hepatic regulators induced by energetic challenge that could be leveraged to counteract pathological lipid accumulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>Integrative transcriptomic analyses were performed across multiple physiological energetic challenges, including cold exposure, \u03b23\u2010adrenergic activation, fasting and exercise, to identify conserved hepatic energy\u2010responsive genes. The functional role of Galectin\u20104 (LGALS4) was investigated using hepatocyte\u2010specific gain\u2010 and loss\u2010of\u2010function approaches in high\u2010fat diet (HFD)\u2010fed mice and primary hepatocytes. Mitochondrial function was assessed via Seahorse metabolic flux analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      LGALS4 emerged as a conserved hepatic factor induced by energetic challenge but suppressed during chronic nutrient excess and in human MASLD liver samples. Hepatocyte\u2010specific overexpression of\n                      <jats:italic>Lgals4<\/jats:italic>\n                      markedly attenuated HFD\u2010induced hepatic steatosis and reduced hepatic triglyceride accumulation, with limited effects on systemic glucose tolerance or insulin sensitivity. Conversely,\n                      <jats:italic>Lgals4<\/jats:italic>\n                      knockdown exacerbated lipid accumulation and impaired fatty acid oxidation (FAO) gene expression in hepatocytes. Mechanistically, LGALS4 increased AMPK and ACC phosphorylation and upregulated the PGC1\u03b1\u2013PPAR\u03b1 fatty acid oxidation programme, leading to enhanced mitochondrial oxidative capacity and reduced lipid accumulation in hepatocytes. These effects were largely abolished by AMPK inhibition, supporting an AMPK\u2010dependent mechanism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>LGALS4 is an energy\u2010responsive hepatic regulator that protects against steatosis by promoting AMPK\u2010dependent fatty acid oxidation. These findings identify LGALS4 as a potential metabolically selective target for MASLD treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.70989","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T04:02:27Z","timestamp":1781150547000},"page":"7875-7891","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatic\n                    <scp>LGALS4<\/scp>\n                    Alleviates Diet\u2010Induced Steatosis by Promoting\n                    <scp>AMPK<\/scp>\n                    \u2010Dependent Fatty Acid Oxidation"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3546-946X","authenticated-orcid":false,"given":"Die","family":"Hu","sequence":"first","affiliation":[{"name":"Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Endocrinology and Metabolism Zhongshan Hospital, Fudan University  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