The role and therapeutic potential of nanotechnology-mediated ferroptosis regulation in myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis and an increased risk of progression to acute myeloid leukemia (AML). Patients with MDS often develop progressive systemic iron overload due to ineffective erythropoiesis, dysregulated hepcidin expression, and repeated blood transfusions. Excess free iron promotes reactive oxygen species generation through the Fenton reaction, resulting in persistent oxidative stress within the bone marrow microenvironment. These abnormalities are closely associated with ineffective hematopoiesis. Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. In MDS, ferroptosis appears to play a dual role. In lower-risk disease settings characterized by ineffective erythropoiesis and anemia, ferroptosis-related injury in erythroid-lineage cells may exacerbate ineffective erythropoiesis. In contrast, in higher-risk or clonally progressive disease settings, selective induction of ferroptosis in malignant clonal cells may represent a potential therapeutic strategy. However, current ferroptosis-targeting agents still face several limitations, including poor water solubility, low stability in vivo, insufficient bone marrow targeting, and possible toxicity to normal tissues. Nanotechnology may offer a promising approach to address these challenges. Nanocarriers can improve bone marrow targeting through surface modification and optimized physicochemical properties, while also enabling controlled drug release and co-delivery of multiple therapeutic agents to enhance efficacy and reduce side effects. This review summarizes the role of ferroptosis in the pathogenesis and treatment of MDS, discusses the major challenges in current ferroptosis-based therapies, and highlights the opportunities and challenges of nanotechnology-mediated ferroptosis regulation as a potential future strategy for precision treatment of MDS.