FeDx-SF@βE assembly for AML treatment via GATA1/SLC40A1 pathway-mediated iron homeostasis disorder

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by rapid progression, therapeutic resistance, and poor prognosis. Inducing ferroptosis in AML cells represents a promising therapeutic strategy. In this study, transcriptomic analyses first revealed that ferroptosis-associated transcriptional states were closely associated with prognosis and ex vivo drug-response heterogeneity in AML, providing a rationale for ferroptosis-oriented therapeutic design. Based on these findings, and further supported by a transcriptome-based target-scoring strategy, β-elemene (βE), a clinically used natural compound derived from traditional Chinese medicine, was selected as a candidate ferroptosis-related agent. We subsequently developed a nanodelivery system, designated FeDx-SF@βE, based on alcohol-induced silk fibroin (SF) folding to co-deliver ferric dextran (FeDx) and βE. The resulting nanoparticles exhibited a uniform particle size of 182.3 nm, favorable colloidal stability, and sustained drug release behavior. In vitro studies demonstrated efficient cellular uptake of FeDx-SF@βE by AML cells, leading to significantly inhibited cell viability. Pharmacological cell-death inhibitor rescue experiments showed that ferrostatin-1 produced the most pronounced protective effect, indicating that FeDx-SF@βE-induced AML cell death was predominantly ferroptosis-dependent. Mechanistically, βE-containing treatment suppressed the nuclear translocation of the transcription factor GATA1 and downregulated the iron efflux channel SLC40A1. GATA1/SLC40A1 gain- and loss-of-function analyses further demonstrated that activation of this axis attenuated FeDx-SF@βE-induced iron overload and ferroptotic injury, whereas suppression of this axis promoted intracellular iron retention, oxidative stress, lipid peroxidation, and mitochondrial damage. In combination with FeDx-derived iron supply, βE-mediated inhibition of the GATA1/SLC40A1 iron-export axis resulted in intracellular iron overload, glutathione depletion, ROS accumulation, extensive lipid peroxidation, and ferroptosis. Bulk transcriptomic and virtual-cell analyses further supported the involvement of the GATA1/SLC40A1 axis in ferroptosis-associated AML states and linked βE-related transcriptional programs to this regulatory mechanism. In a disseminated AML xenograft model, FeDx-SF@βE exhibited enhanced antileukemic efficacy and favorable biosafety. Collectively, this work provides a combined ferroptosis-oriented nanotherapeutic strategy for AML treatment and highlights the GATA1/SLC40A1 iron-homeostasis axis as a functionally relevant mechanism for ferroptosis-targeted nanomedicine design.