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.

Ferroptosis in Acute Central Nervous System Injuries: The Future Direction?

“…Lipid metabolism is closely linked to the regulation of ferroptosis. The accumulation of lipid peroxidation seems to be a key process in the execution phase, in which PUFAs play an important role ( Stockwell et al, 2017 ; Wenzel et al, 2017 ; Yamada et al, 2020 ). Usually, free PUFAs, especially AA and AdA are esterified to membrane phospholipids [mainly PUFA-containing phosphatidylethanolamines (PEs)].…”

(+)-Clausenamide protects against drug-induced liver injury by inhibiting hepatocyte ferroptosis

“…It is now well-accepted that APAP can induce hepatoxicity through two common forms of cell death, namely apoptosis and necrosis 4 . Notably and intriguingly, a recent study indicated that the third form of cell death, termed ferroptosis, might also contribute to APAP-induced DILI in vitro 5,6 . However, in-depth studies are required to define the key role of ferroptosis in DILI, which will open a new door for developing effective intervention strategies.…”

Ferroptosis in Liver Diseases: An Overview

“…NAPQI binds to GSH and leads to severe depletion of GSH in hepatocytes [ 56 ]. Yamada’s team has recently found that ferroptosis driven by ω-6 PUFAs is associated with acetaminophen-induced ALD [ 57 ]. Besides, ferrostatin-1, DFO and vitamin E could exert a protective effect on hepatocytes by suppressing lipid peroxidation and GSH depletion [ 57 ].…”

“…Yamada’s team has recently found that ferroptosis driven by ω-6 PUFAs is associated with acetaminophen-induced ALD [ 57 ]. Besides, ferrostatin-1, DFO and vitamin E could exert a protective effect on hepatocytes by suppressing lipid peroxidation and GSH depletion [ 57 ]. Moreover, it was recently shown using CRISPR-Cas9 that cytochrome P450 oxidoreductase, which is directly implied in the detoxification of xenobiotics by hemoprotein, was necessary for ferroptotic cell death by upregulating the PUFAs peroxidation [ 58 ].…”

“…In 2017, Wang’s team induced ferroptosis in the liver by administering ferric citrate to –SCL7A11 KO mice lacking xCT of system X c − [ 68 ]. Indeed, –SCL7A11 KO facilitates iron overload-induced ferroptosis due to impaired cystine uptake and increased ROS production [ 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ]. Ferrostatin-1 reversed the iron-overload damage [ 68 ].…”