FDX1 suppresses acute myeloid leukemia progression and reverses cuproptosis resistance via the ROS/p53/ME1 axis

Cuproptosis, a copper-dependent cell death mechanism, holds therapeutic potential in cancer, yet its regulatory pathways in acute myeloid leukemia (AML) remain poorly defined. We demonstrate that elevated serum copper levels correlate with poor prognosis in AML patients. Screening reveals that ferredoxin 1 (FDX1) is significantly downregulated in AML and associated with adverse outcomes. FDX1 loss promoted AML cell proliferation and cuproptosis resistance. Mechanistically, FDX1 enhanced mitochondrial damage and ROS/p53 signaling, which transcriptionally suppressed malic enzyme 1 (ME1). ME1 disrupted mitochondrial NAD + /NADH homeostasis and modulated lipoylated DLAT delipoylation, thereby limiting cuproptosis. ME1 was highly expressed in AML and supported leukemic cell growth, while its inhibition restored cuproptosis sensitivity in FDX1-low cells. Given the elevated serum copper levels in AML and the capacity of ME1 inhibition to reverse cuproptosis resistance induced by low FDX1 expression, the combination of copper ionophores with ME1 inhibitors may represent a potential therapeutic strategy for AML.