An alternative route for β-hydroxybutyrate metabolism supports cytosolic acetyl-CoA synthesis in cancer cells.
Level 5 - mechanism / opinion, no new human data
Preclinical in vitro and animal research
PubMed 40921754 · doi:10.1038/s42255-025-01366-y
What was done
The authors investigated the metabolic routing of beta-hydroxybutyrate in cancer cell lines and preclinical mouse models. They examined the transport of mitochondrial acetoacetate derived from beta-hydroxybutyrate into the cytosol and the role of acetoacetyl-CoA synthetase and thiolase in cytosolic acetyl-CoA generation. In vivo tumor growth was evaluated in male mice bearing orthotopic Kras G12D; Trp53 -/- pancreatic tumors and male mice bearing B16 melanoma tumors under calorie restriction.
What was found
No quantitative data, effect sizes, or statistical metrics were provided in the abstract. Qualitatively, beta-hydroxybutyrate-derived acetoacetate was shunted from mitochondria to the cytosol to generate cytosolic acetyl-CoA via acetoacetyl-CoA synthetase and thiolase, bypassing mitochondrial oxidation even in the presence of excess glucose. This pathway supported tumor proliferation and in vivo growth in pancreatic and melanoma mouse models.
Why it matters
The study uncovers an alternative metabolic pathway by which cancer cells directly convert circulating ketone bodies into cytosolic acetyl-CoA for growth. This mechanism suggests caution regarding dietary interventions that elevate ketone bodies in certain tumor contexts.
Limits
The study is restricted to preclinical cell culture and male mouse models, limiting direct extrapolation to human clinical oncology. The abstract does not disclose sample sizes, exact effect sizes, or statistical confidence intervals.
Cited by
- contradicts Cancer cells cannot metabolize fatty acids or ketone bodies for energy because of defective mitochondrial structure and function.