An alternative route for β-hydroxybutyrate metabolism supports cytosolic acetyl-CoA synthesis in cancer cells.

ABSTRACT: Cancer cells are exposed to diverse metabolites in the tumour microenvironment that are used to support the synthesis of nucleotides, amino acids and lipids needed for rapid cell proliferation. In some tumours, ketone bodies such as β-hydroxybutyrate (β-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 β-OHB metabolism that bypasses the TCA cycle to generate cytosolic acetyl-CoA. We show that in cancer cells that can metabolize ketones, β-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it

SUBMITTER: Kaluba FC 

PROVIDER: S-EPMC12552118 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature