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Oridonin (Ori), a covalent NLRP3\u2010inflammasome inhibitor, ameliorates APAP\u2010induced ALI through an unclear molecular mechanism. This study found that Ori decreased hepatic cytochrome P450 2E1 level and increased glutathione content to prevent APAP metabolism, and then reduced the necrotic area, improved liver function, and inhibited APAP\u2010induced proinflammatory cytokines and oxidative stress. Ori also decreased activating transcription factor 4 (ATF4) protein levels and increased peroxisome proliferator\u2010activated receptor\u2010\u03b3 coactivator\u20101\u03b1 (PGC\u20101\u03b1) to reduce APAP\u2010induced endoplasmic reticulum stress activation and mitochondrial dysfunction. Furthermore, western blot and luciferase assay found that ATF4 inhibited transcription in the PGC\u20101\u03b1 promoter \u2212507 to \u2212495 region to reduce PGC\u20101\u03b1 levels, while ATF4 knockdown neutralized the hepatoprotective effect of Ori. Molecular docking showed that Ori bound to ATF4's amino acid residue glutamate 302 through 6, 7, and 18 hydroxyl bands. Our findings demonstrated that Ori prevented metabolic activation of APAP and further inhibited the ATF4\/PGC\u20101\u03b1 pathway to alleviate APAP overdose\u2010induced hepatic toxicity, which illuminated its potential therapeutic effects on ALI.<\/jats:p>","DOI":"10.1002\/ddr.22024","type":"journal-article","created":{"date-parts":[[2022,12,26]],"date-time":"2022-12-26T03:15:55Z","timestamp":1672024555000},"page":"211-225","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Oridonin ameliorates acetaminophen\u2010induced acute liver injury through ATF4\/PGC\u20101\u03b1 pathway"],"prefix":"10.1002","volume":"84","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4222-3985","authenticated-orcid":false,"given":"Dongsheng","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Chinese Medicine The First Affiliated Hospital of Zhengzhou University Zhengzhou 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