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Mitochondrial dysfunction, particularly imbalances in mitochondrial fusion and fission, plays a crucial role in MASLD progression. Irisin, an exercise\u2010induced myokine, is involved in lipid metabolism, though its precise mechanisms of action remain unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An irisin\u2010Fc fusion protein was prophylactically administered to mice with high\u2010fat diet (HFD)\u2013induced MASLD for 12\u2009weeks. Liver tissues were analyzed using oil red O staining and hepatic and serum lipid profiling to evaluate irisin's therapeutic efficacy. Expression levels of proteins involved in fatty acid metabolism and mitochondrial dynamics were assessed. In palmitate (PA)\u2010treated HepG2 cells, mitochondrial morphology was analyzed, and fatty acid uptake was determined through colocalization of fluorescently labeled PA with mitochondria. PKA activity and SIRT3 expression were validated using a PKA agonist\/inhibitor and SIRT3 overexpression or knockdown via plasmid transfection and siRNA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Irisin significantly reduced lipid accumulation in HFD\u2010induced MASLD mouse models and PA\u2010treated HepG2 cells. These effects were associated with enhanced mitochondrial fusion, indicated by increased expression of mitofusin 2 and optic atrophy type 1 and reduced excessive fission, evidenced by decreased activation of dynamin\u2010related protein 1. These changes were mediated partly through PKA\/SIRT3\/mTOR pathway activation, which facilitated mitochondrial fatty acid uptake and \u03b2\u2010oxidation while inhibiting lipogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results demonstrate the protective role of irisin in alleviating hepatic steatosis by regulating mitochondrial dynamics. These findings provide valuable evidence of the antisteatogenic mechanisms of irisin and its therapeutic potential for MASLD management.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jgh.16950","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T05:58:32Z","timestamp":1743746312000},"page":"1616-1630","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Irisin Alleviates Impaired Mitochondrial Fusion via Enhancing PKA\/SIRT3\/mTOR Pathway in Hepatic Steatosis"],"prefix":"10.1111","volume":"40","author":[{"given":"Jia","family":"Li","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, Huashan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Huashan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Huashan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anran","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Huashan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunzhi","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Huashan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Huashan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Huashan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Zhang","sequence":"additional","affiliation":[{"name":"Innogen Pharmaceutical Co. 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