Ferritinophagy supports iron-dependent metabolic reprogramming in Tet2-mutant CH. HSPCs harboring Tet2 mutations exhibit elevated iron demand and turnover, leading to enhanced mitochondrial adenosine triphosphate production, increased proliferation, and a competitive advantage over Tet2-WT HSPCs. Enhanced iron supply is sustained in part by the mobilization of intracellular iron stores through ferritinophagy. Disruption of this pathway either genetically, by targeting the ferritinophagy receptor NCOA4, or pharmacologically, by inhibiting lysosomal iron release using ironomycin, reduces the labile iron pool, impairs OXPHOS, and abolishes the competitive advantage of Tet2-mutant HSPCs. WT, wild-type. Figure created with BioRender.com.