Abstract
Acute myeloid leukemia (AML) has a poor prognosis and is associated with aberrant NF-κB activation, providing a tumor-selective therapeutic window. Therefore, a combination therapy involving FDA-approved ferumoxytol (Feraheme, FeNPs) and NF-κB-responsive GBA interference was developed in this study. GBA is a key enzyme that maintains lysosomal lipid metabolism and membrane composition homeostasis. Its inhibition causes lysosomal storage disorders and functional impairment, leading to the release of labile iron that contributes mainly to ferroptosis in AML. Using a miR30-based shRNA system, we constructed and screened an AML-specific GBA-knockdown plasmid, pNM6-miGBA (miGBA). Low-dose FeNPs promote the Fenton reaction and amplify an NF-κB positive feedback loop, markedly enhancing miGBA-mediated cytotoxicity without activating NF-κB in normal cells. Detection of ferroptosis biomarkers, transmission electron microscopy, and RNA-seq confirmed that the synergistic mechanism of FeNPs and miGBA involves ferroptosis. The combination significantly prolonged survival in AML-bearing mice and produced no notable toxicity to major organs, hematologic parameters, or liver and kidney function tests. In summary, combination therapy with FeNPs and miGBA achieves potent anti-AML efficacy with favorable in vivo safety, and has potential for clinical development.