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

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.