• TP53-mutant AML cells show increased resistance to cytarabine-induced cytotoxicity compared to TP53-wild-type cells, and reducing TP53 expression in wild-type cells diminishes sensitivity to cytarabine.
• Iron overload suppresses the TP53/BCL2/BAX signaling pathway, counteracting cytarabine-induced apoptosis in AML cells.
• TFR1 mediates iron entry into TP53 wild-type AML cells, contributing to iron-mediated cytarabine resistance.
• These findings reveal a novel mechanism linking iron overload to chemoresistance in AML, offering potential therapeutic targets to overcome drug resistance.