Hepatocyte HIF-2α Aggravates NAFLD by Inducing Ferroptosis through Increasing Extracellular Iron.

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Recent research has illuminated the pivotal role of the hypoxia-inducible factor-2α (HIF-2α) / peroxisome proliferator-activated receptor alpha (PPARα) pathway in non-alcoholic fatty liver disease (NAFLD) progression. Meanwhile, HIF-2α was reported that involved in iron regulation, and aberrant iron distribution derived liver lipogenesis. Therefore, we hypothesize that HIF-2a exacerbates fatty liver by affecting iron distribution. To substantiate this hypothesis, we utilized liver-specific HIF-2α knockout mice and the LO2 cell line with overexpressed HIF-2α. HIF-2α overexpression (OE) was induced via lentiviral infection, followed by exposure to free fatty acids (FFA) and deferoxamine (DFO). In animal experiments, hepatic HIF-2α knockout resulted in lower liver lipid levels, lower liver weight, and higher serum iron levels. Enrichment in autophagy, ferroptosis, and the PI3K-AKT pathway was demonstrated through KEGG analysis in the liver of mice. In vitro experiments showed that HIF-2α increased supernatant iron. In the HIF-2α OE group, the addition of FFA led to decreased levels of reduced glutathione (GSH) and glutathione peroxidase 4 (GPX4) protein, along with increased lipid peroxidation (LPO), cellular lipid droplets, and triglyceride content. Impressively, DFO intervention decreased supernatant iron, reversed these changes by increasing GSH and GPX4 levels, and simultaneously reduced LPO levels, cellular lipid droplets, and triglyceride content. Additionally, the expression of proteins related to β-oxidation increased, and lipid deposition in hepatocytes improved, which may be associated with the PI3K/AKT pathway. In summary, our findings suggest that HIF-2α-mediated iron flux enhances NAFLD cell susceptibility to ferroptosis, thereby impacting lipid metabolism-related genes and contributing to lipid accumulation.