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Nuclear factor erythroid 2\u2010related factor 2 (Nrf2) is a key regulator of ferroptosis. However, if Nrf2 modulates ACLF through ferroptosis remains unknown. Here, the liver tissues of ACLF patients were collected and murine models of ACLF using carbon tetrachloride, D\u2010galactosamine, and lipopolysaccharide as well as an H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>\u2010induced hepatocyte injury model were established. Upon ACLF, livers exhibited key features of ferroptosis, including lipid peroxidation (increase in malondialdehyde whereas a decrease in glutathione and nicotinamide adenine dinucleotide phosphate), and increased mRNA expression of prostaglandin\u2010endoperoxide synthase\u20102 (PTGS2). Ferroptosis inducer RSL\u20103 treatment aggravated liver damage, while ferroptosis inhibitor Ferrostatin\u20101 administration alleviated ACLF severity, manifesting with improved liver histopathological lesions and reduced serum ALT and AST. Compared with normal liver tissue, Nrf2 was upregulated in ACLF patients and murine models. Pharmacological activation of Nrf2 (Bardoxolone Methyl) attenuated liver damage, prevented lipid peroxidation, upregulated PTGS2 mRNA expression, and improved ferroptosis\u2010specific mitochondrial morphology in vivo. In contrast, Nrf2 inhibitor ML385 exacerbated lipid peroxidation and liver injury. Collectively, Nrf2 plays a protective role in ACLF progression through repressing ferroptosis, which provides promising therapeutic cues for ACLF.<\/jats:p>","DOI":"10.1155\/2022\/4505513","type":"journal-article","created":{"date-parts":[[2022,4,16]],"date-time":"2022-04-16T20:20:09Z","timestamp":1650140409000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Nrf2\u2010Mediated Ferroptosis Inhibition Exerts a Protective Effect on Acute\u2010on\u2010Chronic Liver 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