Multiple mechanisms underlie GADD45A loss-mediated in LGR4/HOXA9-driven AML. In LGR4/HOXA9-driven AML cells, LGR4 activation suppresses GADD45A expression, subsequently promoting the self-renewal and stemness of LSCs through the Wnt signaling activation and suppression of endogenous ROS accumulation. Additionally, GADD45A loss confers ferroptosis resistance in LSCs by impeding iron storage. Concurrently, GADD45A loss contributes to AML leukemogenesis by inducing genomic instability and gene mutations.