Potential diagnostic, prognostic, and therapeutic implications of ferroptosis in myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a heterogeneous group of malignant disorders originating from hematopoietic stem cells. Ineffective hematopoiesis, peripheral blood cytopenia, immune disorder, and a high risk of progression to acute myeloid leukemia (AML) are typical characteristics of MDS. The diagnosis and management of MDS is still challenging due to the myriad of other causes of cytopenias and the various clinical presentations of the disease. Moreover, the current therapeutic strategies for MDS have limited efficacy. This emphasizes the importance of exploring novel diagnostic, prognostic, and therapeutic approaches. Ferroptosis is a recently identified distinct form of regulated cell death dependent on iron stores. Iron overload occurs in a considerable percentage of patients with MDS. Many patients with MDS become dependent on blood transfusions and develop transfusional iron overload, which is exacerbated by increased absorption of dietary iron in response to ineffective erythropoiesis. In case of iron overload, the non-transferrin-bound iron in the serum reacts with hydrogen peroxide and generates reactive oxygen species (ROS). Moreover, iron overload can result in a reduction of Glutathione (GSH) levels and decreased activity of Glutathione peroxidase 4 (GPX4), which results in uncontrolled iron-dependent lipid peroxidation and a toxic accumulation of lethal ROS within the cell, which ultimately triggers ferroptosis. Recent studies have identified several ferroptosis-related genes (FRGs) that may serve as biomarkers for diagnosis and prognosis in MDS. Moreover, it has been documented that targeting ferroptosis could be a potential strategy for treating MDS, particularly targeting iron metabolism, GSH/ suppressing system Xc-, and FRGs to induce ferroptosis may provide therapeutic benefits to MDS patients. Therefore, this review summarizes the current knowledge on the diagnostic, prognostic, and therapeutic implications of ferroptosis and its related genes in MDS.