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It is established that the predominant mode of hepatocyte cell death after an APAP overdose is through necrosis, and it is now recognized that this occurs through regulated pathways involving RIP kinases. These kinases, along with the pseudo-kinase MLKL, are central players in classical necroptotic cell death. Despite the skepticism regarding the role of necroptosis in APAP-induced liver injury, recent research demonstrating necroptosis-independent roles for MLKL led us to re-examine the role of this pseudo-kinase in APAP pathophysiology. Treatment of Mlkl\u2212\/\u2212 mice with a moderate (300\u2009mg\/kg) overdose of APAP resulted in an exacerbation of liver injury at 6- and 12-h post-APAP as evidenced by elevated plasma alanine aminotransferase activities, and extensive necrosis accompanied by diminished glutathione levels. Interestingly, these differences between Mlkl\u2212\/\u2212 and wild-type mice were negated at the 24-h mark, previously scrutinized by others. At 6 and 12\u2009h post-APAP, Mlkl\u2212\/\u2212 mice exhibited augmented translocation of AIF and Endonuclease G without affecting JNK activation, suggesting enhanced mitochondrial permeability transition in the absence of MLKL. Lack of MLKL also impacted autophagy, the unfolded protein response and endoplasmic reticulum stress, with decreased levels of p62 and LC3B and increased expression of CHOP and GRP78 at 6\u2009h post-APAP. In essence, our findings illuminate a noncanonical role for MLKL in the early phases of APAP-induced liver injury, warranting further exploration of its influence on APAP pathophysiology.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaf022","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T23:20:17Z","timestamp":1740007217000},"page":"220-232","source":"Crossref","is-referenced-by-count":2,"title":["Mixed lineage kinase domain-like protein deficiency exacerbates early injury in a mouse model of acetaminophen hepatotoxicity"],"prefix":"10.1093","volume":"205","author":[{"given":"Giselle","family":"Sanchez-Guerrero","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center , Kansas City, KS 66160,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5327-9020","authenticated-orcid":false,"given":"David 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