Ketogenic diet accelerates intestinal tumorigenesis in mice via dietary lipid oxidation, not ketone metabolites (nature.com)

• KD increases tumor burden and reduces survival in Apc mutant mice, independent of ketone bodies.
• Genetic manipulation of Hmgcs2 (ketogenic enzyme) or Bdh1/2 (ketolysis) does not alter tumorigenesis on KD.
• PPARα/δ/γ signaling and CPT1A-dependent fatty acid oxidation are required for KD-driven intestinal stem cell expansion and adenoma formation.
• Lipidomics and scRNA-seq data support the role of dietary fatty acids, not ketones, in promoting cancer.

"A Nature study using mouse models of familial adenomatous polyposis shows that a ketogenic diet (KD) accelerates intestinal tumor growth and reduces survival. Contrary to expectations, this effect is independent of ketone bodies. Using genetic and dietary manipulations, the authors demonstrate that tumorigenesis is driven by dietary lipids through PPAR signaling and CPT1A-dependent fatty acid oxidation, not by ketogenesis. Combined loss of PPARα/δ/γ or inhibition of CPT1A attenuates KD-driven stem cell expansion and adenoma formation. The findings highlight dietary lipid content as a key mediator of cancer risk in genetically susceptible populations."