{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T14:43:52Z","timestamp":1773931432487,"version":"3.50.1"},"reference-count":62,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["JP25840035"],"award-info":[{"award-number":["JP25840035"]}]},{"name":"JSPS KAKENHI","award":["JP16K18419"],"award-info":[{"award-number":["JP16K18419"]}]},{"name":"JSPS KAKENHI","award":["JP19K07642"],"award-info":[{"award-number":["JP19K07642"]}]},{"name":"Hiroshima Jogakuin University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Inflammation is widely viewed as a driver of hepatocellular carcinoma (HCC), yet inflammatory signaling also reshapes hepatic xenobiotic metabolism. Here, we established transgenic (Tg) IKK\u03b2\u0394hep mice (Tg-IKK\u03b2\u0394hep), which combine hepatocyte-specific IKK\u03b2 deletion with liver expression of a nuclear, kinase-inactive IKK\u03b2 mutant (NLS-IKK\u03b2KN). Tg-IKK\u03b2\u0394hep mice developed spontaneous chronic hepatitis and progressive fibrosis but were strikingly resistant to diethylnitrosamine (DEN)-induced hepatocarcinogenesis, with markedly reduced tumor multiplicity and total tumor burden. Despite persistent inflammatory injury, DEN-triggered oxidative DNA damage and p53 activation were markedly attenuated, compatible with reduced tumor initiation. Transcriptomic and biochemical analyses revealed broad repression of xenobiotic-metabolizing cytochrome P450 genes, including the pericentral enzyme CYP2E1, accompanied by reduced CYP2E1 protein abundance. This was associated with impaired HNF4\u03b1\u2013PXR\u2013CAR transcriptional output and reduced HNF4\u03b1 occupancy at target promoters. Acute TNF\u03b1 or IL-1\u03b2 exposure recapitulated this repression, in part through reduced PGC-1\u03b1 expression and decreased RNA polymerase II recruitment to target promoters. In parallel, pericentral xenobiotic metabolism was blunted, a change that could plausibly diminish DEN bioactivation and genotoxic stress. Together, these findings support a \u201cmetabolic gatekeeping\u201d model in which chronic inflammation can constrain chemical hepatocarcinogenesis by attenuating carcinogen-metabolizing capacity.<\/jats:p>","DOI":"10.3390\/cells15060546","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T11:50:36Z","timestamp":1773921036000},"page":"546","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inflammation-Driven Downregulation of CYP2E1 Is Associated with Attenuated Diethylnitrosamine (DEN)-Induced Hepatocarcinogenesis"],"prefix":"10.3390","volume":"15","author":[{"given":"Yoshihiro","family":"Tsuchiya","sequence":"first","affiliation":[{"name":"Department of Nutrition and Health, Faculty of Human Life Studies, Hiroshima Jogakuin University, Hiroshima 732-0063, Japan"},{"name":"Department of Molecular Medical Science, Graduate School of Biomedical Science, Hiroshima University, Hiroshima 734-8553, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2856-1518","authenticated-orcid":false,"given":"Yusuke","family":"Sotomaru","sequence":"additional","affiliation":[{"name":"Natural Science Center for Basic Research and Development, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akinori","family":"Kanai","sequence":"additional","affiliation":[{"name":"Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0246-1594","authenticated-orcid":false,"given":"Shin","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, School of Medicine, Yokohama City University, Yokohama 236-0004, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideaki","family":"Kamata","sequence":"additional","affiliation":[{"name":"Department of Molecular Medical Science, Graduate School of Biomedical Science, Hiroshima University, Hiroshima 734-8553, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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