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Ketogenesis promotes leukemia development by inhibiting ferroptosis in leukemic stem cells [ATAC-Seq]

GSE325783 Mus musculus Genome binding/occupancy profiling by high throughput sequencing 4 samples Submitted 2026/03/29 Platform GPL34290
Summary
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) engage elevated ketogenesis, driven by fatty acid oxidation (FAO), to produce D-β-hydroxybutyrate (BHB). LSCs express high levels of 3-hydroxymethylglutaryl-CoA synthase 2 (HMGCS2), the rate-limiting enzyme in ketogenesis than 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.
Published in
A ketogenesis-ferroptosis axis maintains leukemic stem cell survival and leukemia progression
Han X, Wang K, Ma W et al. · Cell stem cell 2026 · PMID 42119562 · doi:10.1016/j.stem.2026.04.013
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Also filed as BioProject PRJNA1441601 and SRA study SRP686031. Searching any of these in the dataset finder brings you back here.

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