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Autophagy is a degradative process by which various cargoes are collected by the autophagic receptors such as p62\/SQSTM1\/Sequestosome\u20101 for lysosomal degradation. Here, we investigated the protective role of p62\u2010dependent autophagy in paracetamol\u2010induced liver injury.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Paracetamol\u2010induced hepatotoxicity was induced by a single i.p. injection of paracetamol (500\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>) in C57\/BL6 male mice. YTK\u20102205 (20\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>), a p62 agonist targeting ZZ domain, was co\u2010 or post\u2010administered with paracetamol. Western blotting and immunocytochemistry were performed to explore the mechanism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>N\u2010terminal arginylation of the molecular chaperone calreticulin retro\u2010translocated from the endoplasmic reticulum (ER) was induced in the livers undergoing paracetamol\u2010induced hepatotoxicity, and YTK\u20102205 exhibited notable therapeutic efficacy in acute hepatotoxicity as assessed by the levels of serum alanine aminotransferase and hepatic necrosis. This efficacy was significantly attributed to accelerated degradation of ubiquitin (Ub) conjugates as well as damaged mitochondria (mitophagy) and endoplasmic reticulum (ER\u2010phagy). In primary murine hepatocytes treated with paracetamol, YTK\u20102205 induced the co\u2010localization of p62<jats:sup>+<\/jats:sup>LC3<jats:sup>+<\/jats:sup> phagophores to the sites of mitophagy and ER\u2010phagy. A similar activity of YTK\u20102205 was observed with <jats:italic>N<\/jats:italic>\u2010acetyl\u2010<jats:italic>p<\/jats:italic>\u2010benzoquinone imine, a putative toxic metabolite of paracetamol in Hep3B cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Our results elucidated that p62\u2010dependent autophagy plays a key role in the removal of cytotoxic materials such as damaged mitochondria in paracetamol\u2010induced hepatotoxicity. Small molecule ligands to p62 may be developed into drugs to treat this pathological condition.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16004","type":"journal-article","created":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T15:43:41Z","timestamp":1670427821000},"page":"1247-1266","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Mitophagy and endoplasmic reticulum\u2010phagy accelerated by a p62 ZZ ligand alleviates paracetamol\u2010induced hepatotoxicity"],"prefix":"10.1111","volume":"180","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3687-8475","authenticated-orcid":false,"given":"Hee\u2010Yeon","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Biochemistry, College of Medicine Ewha Womans University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee\u2010Soo","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, College of Medicine Ewha Womans University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7273-1780","authenticated-orcid":false,"given":"Ah Jung","family":"Heo","sequence":"additional","affiliation":[{"name":"Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine Seoul National University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eui Jung","family":"Jung","sequence":"additional","affiliation":[{"name":"Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine Seoul National University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang Hoon","family":"Ji","sequence":"additional","affiliation":[{"name":"Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine Seoul National University  Seoul 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