Glutathione peroxidase 4 (GPX4) is a key factor in ferroptosis, which is involved in ischemia-reperfusion injury. However, little is known about its role in hepatic ischemia-reperfusion injury (HIRI). This study aimed to investigate the role of GPX4 methylation in ferroptosis during HIRI.
For the in vivo experiments, an ischemia-reperfusion model was created by subjecting mice to simulated HIRI. Ferroptosis occurrence, GPX4 promoter methylation, and global methylation levels were then assessed.
Ferroptosis was observed in oxygen and glucose deprivation, characterized by a significant decrease in cellular viability ( P < 0.05), an increase in lipid peroxidation ( P < 0.01), iron overload ( P < 0.05), and down-regulation of GPX4 ( P < 0.05). This ferroptosis was exacerbated by GPX4 knockdown ( P < 0.01) and mitigated by exogenous glutathione ( P < 0.01). Similarly, ferroptosis was evident in mice subjected to HIRI, with a down-regulation of GPX4 mRNA and protein expression (all P < 0.01), and an upregulation of acyl-CoA synthetase long-chain family member 4 mRNA and protein (all P < 0.01), as well as prostaglandin-endoperoxide synthase 2 mRNA and protein expression (all P < 0.05). Methylation levels increased, evidenced by upregulation of DNA methylation transferase expression ( P < 0.05) and down-regulation of Ten-eleven translocation family demethylases ( P < 0.01), along with an upregulation of GPX4 promoter methylation.
Ferroptosis may be the primary mode of cell death in hepatocytes following ischemia-reperfusion injury. The methylation of the GPX4 promoter and elevated levels of global hepatic methylation are involved in the regulation of ferroptosis.
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https://www.xiahepublishing.com/2310-8819/JCTH-2024-00135
The study was recently published in the Journal of Clinical and Translational Hepatology .
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Journal of Clinical and Translational Hepatology
GPX4 Promoter Hypermethylation Induced by Ischemia/Reperfusion Injury Regulates Hepatocytic Ferroptosis
18-Oct-2024