TCDD Induces Hepatocytes Lipid Deposition via Downregulation of MFN2

ABSTRACT The persistent environmental pollutant 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) has been implicated in hepatic lipid metabolism disorders and steatosis. However, the precise mechanisms underlying TCDD‐induced hepatic lipid deposition remain incompletely elucidated. Mitofusin 2 (MFN2), a key mitochondrial dynamics protein, plays a critical role in lipid metabolism, as its deficiency leads to metabolic dysregulation. In this study, we investigate the role of MFN2 in TCDD‐induced lipid deposition. Our findings demonstrate that TCDD exposure significantly reduces MFN2 protein expression both in vivo and in vitro, while concomitantly decreasing mitochondrial membrane potential and increasing reactive oxygen species (ROS) levels in Huh7 cells. Notably, overexpression of MFN2 effectively mitigates TCDD‐induced pathological effects, preventing lipid accumulation, restoring mitochondrial membrane potential, and reducing ROS levels. Mechanistically, although TCDD does not alter the MFN2 mRNA expression, it promotes protein degradation through enhanced ubiquitination in vitro. These findings demonstrate that TCDD induces lipid accumulation in Huh7 cells through ubiquitination‐mediated degradation of MFN2. Our study thus identifies MFN2 as a novel target in TCDD‐induced hepatic steatosis.