Ferroptosis driven by radical oxidation of n-6 polyunsaturated fatty acids mediates acetaminophen-induced acute liver failure
| Autor: | Kiyotaka Nakagawa, Koichi Mizuta, Shuntaro Hara, Ariunaa Sampilvanjil, Naohiro Sata, Masafumi Takahashi, Sachiko Watanabe, Takanori Komada, Tadayoshi Karasawa, Hiroaki Kimura, Junya Ito, Naoya Yamada, Yasunaru Sakuma, Hiroshi Kuwata, Ryo Kamata |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Physiology alpha-Tocopherol Phenylenediamines Pharmacology Antioxidants Lipid peroxidation chemistry.chemical_compound 0302 clinical medicine Mice Knockout chemistry.chemical_classification Cyclohexylamines lcsh:Cytology digestive oral and skin physiology 3. Good health Deferoxamine medicine.anatomical_structure Liver 030220 oncology & carcinogenesis Hepatocyte Arachidonic acid Oxidation-Reduction Polyunsaturated fatty acid medicine.drug Immunology Iron Chelating Agents Article 03 medical and health sciences Cellular and Molecular Neuroscience Lipid oxidation Fatty Acids Omega-6 Coenzyme A Ligases medicine Animals Ferroptosis Humans lcsh:QH573-671 Acetaminophen Hepatotoxicity Cell Biology Glutathione Liver Failure Acute Mice Inbred C57BL Disease Models Animal 030104 developmental biology chemistry Cyclooxygenase 2 Hepatocytes Lipid Peroxidation |
| Zdroj: | Cell Death and Disease, Vol 11, Iss 2, Pp 1-16 (2020) Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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