Effect of ferroptosis inhibitors in a murine model of acetaminophen‐induced liver injury

• Published in: Journal of biochemical and molecular toxicology Vol. 38; no. 8; pp. e23791 - n/a
• Main Authors: Adelusi, Olamide B., Etemadi, Yasaman, Akakpo, Jephte Y., Ramachandran, Anup, Jaeschke, Hartmut
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.08.2024
• Subjects: Acetaminophen; Acetaminophen - adverse effects; Acetaminophen - toxicity; acetaminophen hepatotoxicity; Analgesics; Animal models; Animals; Cell death; Chemical and Drug Induced Liver Injury - drug therapy; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - pathology; Cyclohexylamines - pharmacology; Disease Models, Animal; Ferroptosis; Ferroptosis - drug effects; ferrostatin‐1; Hepatocytes; Hepatotoxicity; Inhibitors; Injury prevention; Iron; Lipid peroxidation; Lipid Peroxidation - drug effects; Lipids; Lipophilic; Liver; Liver diseases; Male; Mice; Mice, Inbred C57BL; Overdose; Peroxidation; Phenylenediamines - pharmacology; Protein transport; Therapeutic targets; Translocation; UAMC‐3203; ferrostatin‐1; UAMC‐3203; ferroptosis; acetaminophen hepatotoxicity; lipid peroxidation
• ISSN: 1095-6670; 1099-0461; 1099-0461
• DOI: 10.1002/jbt.23791

Liver injury caused by acetaminophen (APAP) overdose is the leading cause of acute liver failure in western countries. The mode of APAP‐induced cell death has been controversially discussed with ferroptosis emerging as a more recent hypothesis. Ferroptosis is characterized by ferrous iron‐catalyzed lipid peroxidation (LPO) causing cell death, which can be prevented by the lipophilic antioxidants ferrostatin‐1 and UAMC‐3203. To assess the efficacy of these ferroptosis inhibitors, we used two murine models of APAP hepatotoxicity, APAP overdose alone or in combination with FeSO4 in fasted male C57BL/6J mice. APAP triggered severe liver injury in the absence of LPO measured as hepatic malondialdehyde (MDA) levels. In contrast, ferrous iron co‐treatment aggravated APAP‐induced liver injury and caused extensive LPO. Standard doses of ferrostatin‐1 did not affect MDA levels or the injury in both models. In contrast, UAMC‐3203 partially protected in both models and reduced LPO in the presence of ferrous iron. However, UAMC‐3203 attenuated the translocation of phospho‐JNK through downregulation of the mitochondrial anchor protein Sab resulting in reduced mitochondrial dysfunction and liver injury. Thus, APAP toxicity does not involve ferroptosis under normal conditions. The lack of effects of ferroptosis inhibitors in the pathophysiology indicates that ferroptosis signaling pathways are not relevant therapeutic targets. Under normal conditions, lysosomal ferrous iron facilitates protein nitration by peroxynitrite. In the absence of lipid peroxidation, ferroptosis inhibitors do not protect unless through off‐target effects. Under conditions of iron supplementation, iron facilitates both protein nitration and lipid peroxidation. Under these conditions, UAMC‐3203 but not ferrostatin‐1 protects by additional mechanisms such as modulation of the mitochondrial protein Sab.