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In pancreatic cancer, elevated plasma BCAA levels are observed years before diagnosis, possibly due to increased protein degradation. However, the status of BCAA catabolism in pancreatic cancer remains unclear. Here, we hypothesized that defective hepatic BCAA utilization contributes to this elevation in pancreatic cancer, similar to observations in obesity and diabetes. Consistent with our hypothesis, increased phosphorylation of the hepatic BCAA catabolic enzyme, branched-chain \u03b1-keto acid dehydrogenase (BCKDH), was observed in a murine nerve invasion model with human pancreatic cancer cells, indicative of an inactive state. Notably, this was associated with reduced whole-body BCAA flux, increased skeletal muscle degradation, and elevated plasma BCAA levels. Patients with stage III pancreatic cancer with severe neural invasion exhibited high plasma BCAA and reduced muscle mass. In addition, patients with stage IV pancreatic cancer showed hepatic BCKDH phosphorylation, which correlated with poor prognosis. Overall, these results suggest the potential existence of impaired BCAA catabolism via hepatic BCKDH downregulation in pancreatic cancer.<\/jats:p>","DOI":"10.1038\/s41598-026-47741-x","type":"journal-article","created":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T15:44:58Z","timestamp":1776008698000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Branched-chain amino acid catabolism is potentially deficient in pancreatic cancer with high-neural invasion"],"prefix":"10.1038","volume":"16","author":[{"given":"Hiroki","family":"Michida","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asami","family":"Hagiwara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Kawasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayuka","family":"Kanda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mika","family":"Kawasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachise","family":"Karakawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetaka","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Ikeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Makinoshima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuichi","family":"Mitsunaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,12]]},"reference":[{"key":"47741_CR1","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.ccell.2019.12.011","volume":"37","author":"S Sivanand","year":"2020","unstructured":"Sivanand, S. & Vander Heiden, M. 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Michida, A.H., Y.S., N.K., M. Kanda, M. Kawasaki, and S. K. are employed by Ajinomoto Co. Inc. S.M. reports grants from Ajinomoto, Ono Pharmaceutical, and Pfizer Inc. outside the submitted work; lecture fees from Ono Pharmaceutical, Otsuka Pharmaceutical, and Meiji Seika Pharmaceutical outside the submitted work; and a patent for a biomarker using free plasma amino acids to predict sarcopenia outside the submitted work. M.I. reports grants from Boehringer Ingelheim, Delta-Fly Pharma, N.V., Invitrogen, NIHON SERVIER, and Novartis outside the submitted work; consulting fees from Astellas Pharma, Novartis, and NIHON SERVIER outside the submitted work; and lecture fees from Guardant Health Japan, NIHON SERVIER, Taiho, Nippon Kayaku, and Yakult outside the submitted work. The authors declare no other competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"17012"}}