Yusuf et al report the dependency of LSPC on ALDH3A2; ablation of the enzyme led to LSPC loss, while sparing nonleukemic hematopoietic stem and progenitor cells (HSPCs). ALDH3A2 has known roles in lipid metabolism: (1) highly reactive fatty aldehydes are generated via membrane-associated phospholipid peroxidation. They can act as second messengers but also have cytotoxic effects if generated in abundance. Upon their NAD⁺-dependent oxidation by ALDH3A2 to FAs (2), they participate in the production of more complex lipids (3) or take part in energy production by providing long-chain FAs used for β-oxidation in mitochondria (4). The authors demonstrated increased ALDH3A2 expression in AML (5), likely to resolve increased lipid peroxidation. In addition, they uncovered that ALDH3A2 facilitates the production of (6) a subset of long-chain FAs and (7) NADH (nicotinamide adenine dinucleotide) to (8) suppress hydroxyl radical (•OH)–mediated DNA and protein damage, ensuring LSPCs meet their energetic requirements (presumably via increasing FA oxidation [FAO]), and (9) escape GPX4-dependent ferroptotic cell death.