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In some tumours, ketone bodies such as \u03b2-hydroxybutyrate (\u03b2-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle. Here we identify a non-canonical route for \u03b2-OHB metabolism that bypasses the TCA cycle to generate cytosolic acetyl-CoA. We show that in cancer cells that can metabolize ketones, \u03b2-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into cytosolic acetyl-CoA. This alternative metabolic routing allows \u03b2-OHB to avoid oxidation in the mitochondria and to be used as a major source of cytosolic acetyl-CoA, even when other key cytosolic acetyl-CoA precursors such as glucose are available in excess. Finally, we demonstrate that ketone body metabolism, including this alternative AACS-dependent route, can support the growth of mouse\n                    <jats:italic>Kras<\/jats:italic>\n                    <jats:sup>G12D<\/jats:sup>\n                    ;\u2009\n                    <jats:italic>Trp53<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    pancreatic tumours grown orthotopically in the pancreas of male mice, as well as the growth of mouse B16 melanoma tumours in male mice fed a calorie-restricted diet. Together, these data reveal how cancer cells use \u03b2-OHB as a major source of cytosolic acetyl-CoA to support cell proliferation and tumour growth.\n                  <\/jats:p>","DOI":"10.1038\/s42255-025-01366-y","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T11:22:00Z","timestamp":1757330520000},"page":"2033-2044","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["An alternative route for \u03b2-hydroxybutyrate metabolism supports cytosolic acetyl-CoA synthesis in cancer cells"],"prefix":"10.1038","volume":"7","author":[{"given":"Faith C.","family":"Kaluba","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Rogers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Jin","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2176-0431","authenticated-orcid":false,"given":"Rachel \u2018Rae\u2019 J.","family":"House","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Althea","family":"Waldhart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly H.","family":"Sokol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel R.","family":"Daniels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron J.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9580-5105","authenticated-orcid":false,"given":"Joseph","family":"Longo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6591-029X","authenticated-orcid":false,"given":"Vincent J.","family":"Sartori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1573-9719","authenticated-orcid":false,"given":"Ryan D.","family":"Sheldon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2250-4675","authenticated-orcid":false,"given":"Russell G.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7866-4761","authenticated-orcid":false,"given":"Evan C.","family":"Lien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,8]]},"reference":[{"key":"1366_CR1","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1016\/j.cmet.2016.12.022","volume":"25","author":"P Puchalska","year":"2017","unstructured":"Puchalska, P. & Crawford, P. 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The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}