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Ferroptosis driven by radical oxidation of n-6 polyunsaturated fatty acids mediates acetaminophen-induced acute liver failure.

ABSTRACT: Acetaminophen (APAP) overdose is a common cause of drug-induced acute liver failure. Although hepatocyte cell death is considered to be the critical event in APAP-induced hepatotoxicity, the underlying mechanism remains unclear. Ferroptosis is a newly discovered type of cell death that is caused by a loss of cellular redox homeostasis. As glutathione (GSH) depletion triggers APAP-induced hepatotoxicity, we investigated the role of ferroptosis in a murine model of APAP-induced acute liver failure. APAP-induced hepatotoxicity (evaluated in terms of ALT, AST, and the histopathological score), lipid peroxidation (4-HNE and MDA), and upregulation of the ferroptosis maker PTGS2 mRNA were markedly prevented by the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1). Fer-1 treatment also completely prevented mortality induced by high-dose APAP. Similarly, APAP-induced hepatotoxicity and lipid peroxidation were prevented by the iron chelator deferoxamine. Using mass spectrometry, we found that lipid peroxides derived from n-6 fatty acids, mainly arachidonic acid, were elevated by APAP, and that auto-oxidation is the predominant mechanism of APAP-derived lipid oxidation. APAP-induced hepatotoxicity was also prevented by genetic inhibition of acyl-CoA synthetase long-chain family member 4 or α-tocopherol supplementation. We found that ferroptosis is responsible for APAP-induced hepatocyte cell death. Our findings provide new insights into the mechanism of APAP-induced hepatotoxicity and suggest that ferroptosis is a potential therapeutic target for APAP-induced acute liver failure.

SUBMITTER: Yamada N

PROVIDER: S-EPMC7039960 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis.

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Project description:Acetaminophen (APAP) toxicity is the leading cause of drug-induced liver failure, which is closely related to mitochondrial dysfunction and oxidative damage. Studies in clinical trials and in animal models have shown that omega-3 polyunsaturated fatty acids (n-3 PUFAs) affect the progression of various types of liver damage. Interestingly, the sex-dependent effect of n-3 PUFAs on human health has also been well documented. However, it is unknown whether supplementation of n-3 PUFAs modulates the pathogenesis of APAP-induced liver failure with sex-specificity. Our results showed that both endogenous and exogenous n-3 PUFAs significantly aggravated the APAP-induced liver injury in male mice, whereas the opposite effects were observed in females. In vivo and in vitro studies demonstrated that estrogen contributes to the gender difference in the regulation of n-3 PUFAs on APAP overdose. We found that n-3 PUFA-mediated regulation of hepatic oxidative stress response and autophagy upon APAP challenge is distinct between male and female mice. Moreover, we provided evidence that β-catenin signaling activation is responsible for the sex-dependent regulation of APAP hepatotoxicity by n-3 PUFAs. Together, these findings indicated that supplementation with n-3 PUFAs displays sex-differential effect on APAP hepatotoxicity and could have profound significance in the clinical management for drug-induced liver injury.

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