Abstract

Hepatic ketogenesis generates ketone bodies as an alternative energy source during carbohydrate restriction or ketogenic diets, yet its role in non-hepatic cell types remains poorly defined. Here, we show that leukemic stem cells (LSCs) in acute myeloid leukemia (AML) exhibit elevated ketogenesis, driven by fatty acid oxidation (FAO), to produce β-hydroxybutyrate (BHB). LSCs express high levels of 3-hydroxy-3-methylglutaryl-coenzyme A (CoA) synthase 2 (HMGCS2), the rate-limiting enzyme in ketogenesis, compared with blast cells and normal hematopoietic stem cells (HSCs). Deletion of Hmgcs2 in AML cells markedly decreases BHB levels, disrupts LSC function, and impairs leukemia progression in both mouse and human AML models while largely sparing normal hematopoiesis. Mechanistically, BHB suppresses ferroptosis by limiting pro-ferroptotic phospholipid remodeling through epigenetic regulation of fatty acid desaturase 2 (FADS2). Together, these findings identify autonomous ketogenesis as a critical metabolic program that protects LSCs from ferroptotic cell death and sustains leukemia progression.