IDH3 regulates citrate homeostasis to control metabolic fitness and venetoclax resistance of AML stem cells.

IDH3A-driven citrate accumulation controls metabolic fitness and venetoclax resistance in AML stem cells, with knockdown impairing leukemia maintenance.

• Why it matters: Understanding metabolic dependencies of leukemic stem cells (LSCs) is crucial because they differ from healthy cells and contribute to therapy resistance, impacting patient outcomes.
• What they did: The study used gene expression analysis, knockdown experiments, and clinical data to show that IDH3A is more abundant in LSCs, and its suppression reduces TCA cycle activity, impairing leukemia growth and increasing drug sensitivity.
• The result: Targeting the IDH3A-citrate pathway shifts AML stem cells toward a vulnerable metabolic state, offering a potential strategy to overcome venetoclax resistance and improve treatment efficacy.