Pemt Inhibition‐Mediated Vdac1 Oligomerization Regulates Mitochondrial Dysfunction, Apoptosis, and Inflammation in High‐Fat Diet‐Derived Liver Injury

ABSTRACT

High‐fat diet (HFD)‐induced hepatic injury represents a pathology observed across vertebrates, yet the underlying mechanisms remain incompletely understood. Herein, the present study identifies phosphatidylethanolamine methyltransferase (Pemt), a key enzyme in phosphatidylcholine synthesis, as a critical regulator of mitochondrial homeostasis in HFD‐driven liver injury. Our findings demonstrate that knockdown or knockout of pemt in hepatocytes from large yellow croaker ( Larimichthys crocea ) and in zebrafish ( Danio rerio ) liver markedly induces apoptosis, NOD‐like receptor protein 3 (Nlrp3) inflammasome activation, and mitochondrial dysfunction. Conversely, PEMT overexpression in large yellow croaker hepatocytes effectively attenuates palmitic acid‐induced apoptosis, Nlrp3 inflammasome activation, and mitochondrial dysfunction. Crucially, the present study reveals a direct protein–protein interaction between Pemt and voltage‐dependent anion channel 1 (Vdac1). Notably, VDAC1 overexpression significantly induces reactive oxygen species (ROS)‐dependent apoptosis and Nlrp3 inflammasome activation. Mechanistically, pemt deficiency enhances Vdac1 oligomerization, which in turn triggers apoptosis and Nlrp3 inflammasome activation in hepatocytes. Collectively, our results establish that HFD‐induced downregulation of Pemt promotes mitochondrial dysfunction and Vdac1 oligomerization, thereby exacerbating ROS‐dependent apoptosis and Nlrp3 inflammasome activation, ultimately leading to liver injury. Our findings establish the Pemt‐Vdac1 regulatory axis as a fundamental protective mechanism against overnutrition‐induced liver injury in vertebrates.