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Abnormal Ferroptosis in Myelodysplastic Syndrome
Qi Lv1, Haiyue Niu1, Lanzhu Yue1
1Department of Hematology, General Hospital, Tianjin Medical University, Tianjin, China.
Background:
Ferroptosis is a form of iron-dependent non-apoptotic cell death, with characteristics of loss of the activity of the lipid repair enzyme, glutathione (GSH) peroxidase 4 (GPX4), and accumulation of lethal reactive lipid oxygen species. The mechanism of ferroptosis in myelodysplastic syndrome (MDS) is unclear.
Methods:
Cell viability assay, reactive oxygen species (ROS) assay, GSH assay, and GPX activity assay were performed to study the regulation of ferroptosis in MDS cells obtained from MDS patients, the iron overload model mice, and cell lines.
Results:
The growth-inhibitory effect of decitabine could be partially reversed by ferrostatin-1 and iron-chelating agent [desferrioxamine (DFO)] in MDS cell lines. Erastin could increase the cytotoxicity of decitabine on MDS cells. The level of GSH and the activity of GPX4 decreased, whereas the ROS level increased in MDS cells upon treatment with decitabine, which could be reversed by ferrostatin-1. The concentration of hemoglobin in peripheral blood of iron overload mice was negatively correlated with intracellular Fe2+ level and ferritin concentration. Iron overload (IO) led to decreased viability of bone marrow mononuclear cells (BMMNCs), which was negatively correlated with intracellular Fe2+ level. Ferrostatin-1 partially reversed the decline of cell viability in IO groups. The level of GSH and the activity of GPX4 decreased, whereas the ROS level increased in BMMNCs of IO mice. DFO could increase the level of GSH. Ferrostatin-1 and DFO could increase the GPX4 activity of BMMNCs in IO mice. Ferrostatin-1 could significantly reverse the growth-inhibitory effect of decitabine in MDS patients. Decitabine could significantly increase the ROS level in MDS groups, which could be inhibited by ferrostatin-1 or promoted by erastin. Ferrostatin-1 could significantly reverse the inhibitory effect of decitabine on GSH levels in MDS patients. Erastin combined with decitabine could further reduce the GSH level. Erastin could further decrease the activity of GPX4 compared with the decitabine group.
Conclusion:
Ferroptosis may account for the main mechanisms of how decitabine induced death of MDS cells. Decitabine-induced ROS raise leads to ferroptosis in MDS cells by decreasing GSH level and GPX4 activity.
Insights
Decitabine induces cell death in myelodysplastic syndrome (MDS) by promoting ferroptosis, a process involving iron, reduced glutathione (GSH), and lipid reactive oxygen species. This study clarifies the mechanism of ferroptosis in MDS.
Area of Science:
- Cell Death Mechanisms
- Iron Metabolism
- Oxidative Stress
Background:
- Ferroptosis is iron-dependent cell death linked to GPX4 inactivation and reactive oxygen species accumulation.
- The specific mechanisms of ferroptosis in myelodysplastic syndrome (MDS) remain largely unknown.
Purpose of the Study:
- To investigate the role and regulation of ferroptosis in myelodysplastic syndrome (MDS).
- To elucidate the impact of decitabine treatment on ferroptosis pathways in MDS.
Main Methods:
- Assays for cell viability, reactive oxygen species (ROS), glutathione (GSH), and GPX4 activity were conducted.
- Experiments utilized MDS cell lines, primary MDS cells, and iron overload mouse models.
Main Results:
- Decitabine treatment in MDS cells decreased GSH and GPX4 activity while increasing ROS, characteristic of ferroptosis.
- Ferrostatin-1 and DFO partially reversed decitabine's effects, indicating ferroptosis involvement.
- Iron overload in mice mirrored these changes, with reduced cell viability and altered redox balance.
Conclusions:
- Ferroptosis is a key mechanism underlying decitabine-induced cell death in MDS.
- Decitabine triggers ferroptosis by increasing ROS and reducing GSH levels and GPX4 activity in MDS cells.
