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TGF\u03b21 has been shown to regulate ataxia\u2010telangiectasia mutated (ATM) signaling and DNA repair in other cell types. This study investigates the DNA damage response (DDR) during APAP\u2010induced liver injury, focusing on ATM\u2010mediated regulation of TGF\u03b21 signaling. APAP administration in\u00a0vitro and in\u00a0vivo resulted in DNA damage, increased ATM signaling, accumulation of \u03b3H2AX, and activation of phosphorylated ataxia telangiectasia mutated (pATM) and phosphorylated checkpoint kinase 2 (pChk2). Pretreatment with an ATM inhibitor, KU55933, attenuated APAP\u2010induced hepatocyte damage and resulted in attenuated mothers against decapentaplegic homolog 2\/3 (SMAD2\/3) signaling with no changes in activated TGF\u03b21 levels, suggesting that ATM activation modulates TGF\u03b21 signaling via post\u2010translational mechanisms. APAP was found to promote transforming growth factor beta receptor 2 (TGF\u03b2RII) stabilization through activation of phosphorylated casitas B\u2010lineage lymphoma (p\u2010c\u2010cbl) and subsequent neddylation of TGF\u03b2RII, which was attenuated by inhibitors of ATM signaling or neddylation machinery. In conclusion, APAP\u2010induced hepatic DNA damage activates an ATM\u2010mediated response that enhances TGF\u03b21 signaling through stabilization of TGF\u03b2RII, and inhibition of ATM consequently reduces APAP\u2010induced hepatic injury.<\/jats:p>","DOI":"10.14814\/phy2.70695","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T05:31:09Z","timestamp":1765344669000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ataxia\u2010telangiectasia mutated activation mediates transforming growth factor beta signaling in acetaminophen\u2010induced liver injury in mice"],"prefix":"10.14814","volume":"13","author":[{"given":"Matthew","family":"McMillin","sequence":"first","affiliation":[{"name":"Huffington Department of Education, Innovation &amp; Technology Baylor College of Medicine  Temple Texas USA"},{"name":"Department of Medicine Baylor College of Medicine  Temple Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher S.","family":"Chu","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Toxicology, College of Pharmacy The University of Texas at Austin  Austin Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elaina","family":"Williams","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Toxicology, College of Pharmacy The University of Texas at Austin  Austin Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juliet","family":"Venter","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Toxicology, College of Pharmacy The University of Texas at Austin  Austin Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiersten","family":"Bell","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Toxicology, College of Pharmacy The University of Texas at Austin  Austin Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anca D.","family":"Petrescu","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Toxicology, College of Pharmacy The University of Texas at Austin  Austin Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Mireles","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Toxicology, College of Pharmacy The University of Texas at Austin  Austin Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0511-9778","authenticated-orcid":false,"given":"Sharon","family":"DeMorrow","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Toxicology, College of Pharmacy The University of Texas at Austin  Austin Texas USA"},{"name":"Department of Internal Medicine Dell Medical School, The University of Texas at Austin  Austin Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,12,9]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.44.27678"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1089\/adt.2014.571"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)60274-7"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aan1230"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3727\/105221618X15205260749346"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.22087"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgv079"},{"key":"e_1_2_11_9_1","unstructured":"Chu C. 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