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Branched-chain amino acids (BCAAs) are known to promote skeletal muscle growth in healthy individuals; however, their efficacy in cancer patients remains controversial. In this study, we investigated the effects of BCAAs on cancer-associated sarcopenia to identify the underlying mechanisms that may suppress their effectiveness. In both a mouse cachexia model and an in vitro cachexia model, BCAAs did not significantly reduce oxidative stress, improve oxidative phosphorylation, suppress cytokine production, or enhance muscle mass and maturation, as observed in non-cancer-bearing models. Furthermore, treatment with 5-fluorouracil exacerbated sarcopenia in the mouse cachexia model, independent of tumor weight reduction, and this deterioration was not ameliorated by a BCAA-supplemented diet. The ineffectiveness of BCAAs was attributed to impaired BCAA catabolism, characterized by the decreased expression of branched-chain \u03b1-ketoacid dehydrogenase (BCKD) and increased levels of its inactive phosphorylated form, which were driven by elevated expression of BCKD kinase. These metabolic alterations were induced by high-mobility group box-1 (HMGB1). Notably, caprylic acid reversed these impairments in BCAA metabolism, thereby restoring BCAA efficacy. Our findings suggest that enhancing BCAA metabolism may improve their therapeutic potential in the treatment of cancer-associated sarcopenia.<\/jats:p>","DOI":"10.3390\/cimb47050325","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T09:16:12Z","timestamp":1746090972000},"page":"325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Caprylic Acid Restores Branched-Chain Amino Acid Metabolism in a Mouse Cachexia Model"],"prefix":"10.3390","volume":"47","author":[{"given":"Isao","family":"Kawahara","sequence":"first","affiliation":[{"name":"Department of Molecular Pathology, Nara Medical University School of Medicine, Kashihara 634-8521, Japan"},{"name":"Division of Rehabilitation, Hanna Central Hospital, Ikoma 630-0243, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rina","family":"Fujiwara-Tani","sequence":"additional","affiliation":[{"name":"Department 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