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We show here that pancreas-specific loss of DBT, the E2 subunit of the branched-chain keto-acid dehydrogenase (BCKDH) complex required for BCAA oxidation, strikingly exacerbates premalignant pancreatic intraepithelial neoplasia (PanIN) lesions in KC (\n                  <jats:italic>p48-Cre<\/jats:italic>\n                  ;\n                  <jats:italic>\n                    Kras\n                    <jats:sup>LSL-G12D\/+<\/jats:sup>\n                  <\/jats:italic>\n                  ) mice. However, deletion of upstream enzyme BCAT2 neither phenocopied nor rescued loss of DBT in KC mice, ruling out involvement of both upstream and downstream metabolites as mediators of PanIN promotion. Instead, we observed that DBT deficiency led to loss of the kinase BCKDK, a negative regulator of the BCKDH complex, and that, remarkably, pancreas-specific loss of BCKDK phenocopied DBT deficiency in accelerating PanIN formation. These data thus support a model in which pancreas BCKDK restrains tumorigenesis. In contrast, systemic treatment of KC mice with the BCKDK inhibitor BT2, which inhibits BCKDH phosphorylation across many tissues except the pancreas, reduced PanIN formation and preserved normal acinar area. Together the data reveal the promotion of BCAA catabolism systemically, but not within the pancreas, as a promising intervention strategy to suppress tumor initiation.\n                <\/jats:p>","DOI":"10.1101\/2025.06.10.658925","type":"posted-content","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T16:35:15Z","timestamp":1750091715000},"source":"Crossref","is-referenced-by-count":0,"title":["Opposing effects of systemic and pancreas-specific inhibition of BCKDK on pancreatic carcinogenesis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6996-5367","authenticated-orcid":false,"given":"Michael C.","family":"Noji","sequence":"first","affiliation":[{"name":"Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA"},{"name":"Cardiovascular Institute, University of Pennsylvania, Philadelphia, 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