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We aimed to unveil the molecular pathways involved in triggering ibuprofen\u2010induced ALI, which, at present, remain elusive. First, we investigated activation of essential pathways in human liver sections of ibuprofen\u2010induced ALI. Next, we assessed the cytotoxicity of ibuprofen <jats:italic>in vitro<\/jats:italic> and developed a novel murine model of ibuprofen intoxication. To assess the role of JNK, we used animals carrying constitutive deletion of c\u2010Jun N\u2010terminal kinase 1 (<jats:italic>Jnk1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>) or Jnk2 (<jats:italic>Jnk2<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>) expression and included investigations using animals with hepatocyte\u2010specific Jnk deletion either genetically (<jats:italic>Jnk1<\/jats:italic><jats:sup><jats:italic>\u0394hepa<\/jats:italic><\/jats:sup>) or by siRNA (<jats:italic>siJnk2<\/jats:italic><jats:sup><jats:italic>\u0394hepa<\/jats:italic><\/jats:sup>). We found in human and murine samples of ibuprofen\u2010induced acute liver failure that JNK phosphorylation was increased in the cytoplasm of hepatocytes and other non\u2010liver parenchymal cells (non\u2010LPCs) compared with healthy tissue. In mice, ibuprofen intoxication resulted in a significantly stronger degree of liver injury compared with vehicle\u2010treated controls as evidenced by serum transaminases, and hepatic histopathology. Next, we investigated molecular pathways. PKC\u03b1, AKT, JNK and RIPK1 were significantly increased 8\u00a0h after ibuprofen intoxication. Constitutive <jats:italic>Jnk1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> and <jats:italic>Jnk2<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> deficient mice exhibited increased liver dysfunction compared to wild\u2010type (WT) animals. Furthermore, <jats:italic>siJnk2<\/jats:italic><jats:sup><jats:italic>\u0394hepa<\/jats:italic><\/jats:sup> animals showed a dramatic increase in biochemical markers of liver function, which correlated with significantly higher serum liver enzymes and worsened liver histology, and MAPK activation compared to <jats:italic>Jnk1<\/jats:italic><jats:sup><jats:italic>\u0394hepa<\/jats:italic><\/jats:sup> or WT animals. In our study, cytoplasmic JNK activation in hepatocytes and other non\u2010LPCs is a hallmark of human and murine ibuprofen\u2010induced ALI. Functional <jats:italic>in vivo<\/jats:italic> analysis demonstrated a protective role of hepatocyte\u2010specific <jats:italic>Jnk2<\/jats:italic> during ibuprofen ALI. Copyright \u00a9 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.5174","type":"journal-article","created":{"date-parts":[[2018,9,28]],"date-time":"2018-09-28T01:54:38Z","timestamp":1538099678000},"page":"110-122","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Protective role of c\u2010Jun N\u2010terminal kinase\u20102 (JNK2) in ibuprofen\u2010induced acute liver injury"],"prefix":"10.1002","volume":"247","author":[{"given":"Miguel E","family":"Zoubek","sequence":"first","affiliation":[{"name":"Department of Internal Medicine III University Hospital RWTH Aachen  Aachen Germany"},{"name":"Department of Toxicology, Faculty of Health, Medicine and Life Sciences, School for Nutrition, Toxicology and Metabolism (NUTRIM) Maastricht University  Maastricht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marius 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