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

Résumé fourni par la source

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.

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