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Herein, the present study identifies phosphatidylethanolamine methyltransferase (Pemt), a key enzyme in phosphatidylcholine synthesis, as a critical regulator of mitochondrial homeostasis in HFD\u2010driven liver injury. Our findings demonstrate that knockdown or knockout of\n                    <jats:italic>pemt<\/jats:italic>\n                    in hepatocytes from large yellow croaker (\n                    <jats:italic>Larimichthys crocea<\/jats:italic>\n                    ) and in zebrafish (\n                    <jats:italic>Danio rerio<\/jats:italic>\n                    ) liver markedly induces apoptosis, NOD\u2010like receptor protein 3 (Nlrp3) inflammasome activation, and mitochondrial dysfunction. Conversely, PEMT overexpression in large yellow croaker hepatocytes effectively attenuates palmitic acid\u2010induced apoptosis, Nlrp3 inflammasome activation, and mitochondrial dysfunction. Crucially, the present study reveals a direct protein\u2013protein interaction between Pemt and voltage\u2010dependent anion channel 1 (Vdac1). Notably, VDAC1 overexpression significantly induces reactive oxygen species (ROS)\u2010dependent apoptosis and Nlrp3 inflammasome activation. Mechanistically,\n                    <jats:italic>pemt<\/jats:italic>\n                    deficiency enhances Vdac1 oligomerization, which in turn triggers apoptosis and Nlrp3 inflammasome activation in hepatocytes. Collectively, our results establish that HFD\u2010induced downregulation of Pemt promotes mitochondrial dysfunction and Vdac1 oligomerization, thereby exacerbating ROS\u2010dependent apoptosis and Nlrp3 inflammasome activation, ultimately leading to liver injury. Our findings establish the Pemt\u2010Vdac1 regulatory axis as a fundamental protective mechanism against overnutrition\u2010induced liver injury in vertebrates.\n                  <\/jats:p>","DOI":"10.1002\/advs.76060","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T09:21:46Z","timestamp":1782984106000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pemt Inhibition\u2010Mediated Vdac1 Oligomerization Regulates Mitochondrial Dysfunction, Apoptosis, and Inflammation in High\u2010Fat Diet\u2010Derived Liver Injury"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6963-412X","authenticated-orcid":false,"given":"Xianyong","family":"Bu","sequence":"first","affiliation":[{"name":"Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affair) Key Laboratory of Mariculture (Ministry of Education) Ocean University of China  Qingdao P. 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