Document Type

Article

Publication Date

11-2025

Identifier

DOI: 10.1016/j.tox.2025.154221

Abstract

Acetaminophen (APAP) overdose can cause liver injury and is the leading cause of acute liver failure in Western countries. Hepatocellular necrosis induced by APAP involves the formation of a reactive metabolite, triggering mitochondrial oxidant stress and peroxynitrite formation. Iron-catalyzed protein nitration is critical for mitochondrial dysfunction and cell death in the absence of lipid peroxidation (LPO). However, co-treatment of APAP and ferrous sulfate aggravated protein nitration and liver injury but also triggered extensive LPO (measured as malondialdehyde and hydroxy eicosatetraenoic acid (HETE) species). The objective of this study was to evaluate whether the aggravated injury under these conditions is caused by a combination of protein nitration and LPO or if LPO is now the dominant injury mechanism. To test this, C57BL/6 J mice were co-treated with APAP (300 mg/kg) and a moderate dose of ferrous sulfate (0.15 mmol/kg) for 6 h. Some animals also received a dose of Mito-TEMPO, the mitochondria-targeted SOD mimetic, or minocycline, an inhibitor of mitochondrial iron uptake. Although Mito-TEMPO and minocycline eliminated protein nitration and liver injury after APAP alone, these interventions did not affect LPO and only had a moderate effect on protein nitration and liver injury in the APAP+Fe2+ group, suggesting LPO as the main mechanism of cell death. Consistent with these findings, delayed treatment with clinically relevant antidotes N-acetylcysteine and fomepizole did not reduce LPO or liver injury. Thus, liver injury after APAP+Fe2+ is no longer primarily driven by mitochondrial oxidant stress and peroxynitrite-mediated necrosis but by lipid peroxidation and a ferroptosis-like cell death.

Journal Title

Toxicology

Volume

517

First Page

154221

Last Page

154221

MeSH Keywords

Animals; Acetaminophen; Ferroptosis; Chemical and Drug Induced Liver Injury; Acetylcysteine; Mice, Inbred C57BL; Mice; Male; Lipid Peroxidation; Cell Death; Ferrous Compounds; Liver; Iron; Oxidative Stress; Antidotes

PubMed ID

40518003

Keywords

4-methylpyrazole; N-acetylcysteine; drug hepatotoxicity; ferroptosis; lipid peroxidation; peroxynitrite

Comments

This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Publisher's Link: https://www.sciencedirect.com/science/article/pii/S0300483X25001805?via%3Dihub

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