Hematopoietic protection and mechanisms of ferrostatin-1 on hematopoietic acute radiation syndrome of mice

Abstract

Purpose

Baicalein (an anti-ferroptosis drug) was recently reported to synergistically improve the survival rate of mice following a high dose of total body irradiation with anti-apoptosis and anti-necroptosis drugs. At the same time, our group has demonstrated that ferrostatin-1, a ferroptosis inhibitor, improves the survival rate of a mouse model of hematopoietic acute radiation syndrome to 60% for 150 days (p < .001). These phenomena suggest that ferroptosis inhibition can mitigate radiation damage. In this study, we continued to study the mechanisms by which ferrostatin-1 alleviated radiation-induced ferroptosis and subsequent hematopoietic acute radiation syndrome.

Materials and methods

Male ICR mice (8–10 weeks old) were exposed to doses of 0, 8, or 10 Gy irradiated from a ¹³⁷Cs source. Ferrostatin-1 was intraperitoneally injected into mice 72 h post-irradiation. Bone marrow mononuclear cells (BMMCs) and peripheral blood cells were counted. The changes in iron-related parameters, lipid metabolic enzymes, lipid peroxidation repair molecules (glutathione peroxidase 4, glutathione, and coenzyme Q10), and inflammatory factors (TNF-α, IL-6, and IL-1β) were evaluated using biochemical or antibody techniques.

Results

Ferrostatin-1 increased the number of red and white blood cells, lymphocytes, and monocytes in the peripheral blood after total body irradiation in mice by mitigating the ferroptosis of BMMCs. Total body irradiation induced ferroptosis in BMMCs by increasing the iron and lipid peroxidation levels and depleting the acyl-CoA synthetase long-chain family member 4 (ASCL4), lipoxygenase 15, glutathione peroxidase 4, and glutathione levels. Ferroptotic BMMCs did not release TNF-α, IL-6, or IL-1β at the early stage of radiation exposure. Ferrostatin-1 mitigated the lipid peroxidation of radiation-induced ferroptosis by attenuating increases in levels of hemosiderin and liable iron pool and decreases in levels of ASCL4 and glutathione peroxidase 4.

Conclusions

The onset of total body irradiation-induced ferroptosis in BMMCs involved changes in iron, lipid metabolic enzymes, and anti-lipid peroxidation molecules. Ferrostatin-1 could be a potential radiation mitigation agent by acting on these targets.

Keywords:

• Hematopoietic acute radiation syndrome
• ferrostatin-1
• iron
• lipid metabolic enzyme
• lipid peroxidation repair molecule

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was supported by the Fundamental Research Funds for the Central Universities [numbers NS2020042 and NJ2020017-2]; the National Natural Science Foundation of China [numbers 11575086 and 81571805); the Postdoctoral Science Foundation of China [number 2017M611660]; the Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions; and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Notes on contributors

Xiaohong Zhang

Xiaohong Zhang, PhD. She is a senior experimentalist of the Department of Nuclear Science and Technology, Nanjing University of Aeronautics and Astronautics. Her research interests are in the areas of radiation biology and biodosimetry.

Mengxin Tian

Mengxin Tian, MD. She is a postgraduate of the Department of Nuclear Science and Technology, Nanjing University of Aeronautics and Astronautics. Her research interests are in the area of radiation biology.

Xin Li

Xin Li, MD. She is a postgraduate of the Department of Nuclear Science and Technology, Nanjing University of Aeronautics and Astronautics. Her research interests are in the area of radiation biology.

Chunyan Zheng

Chunyan Zheng, MD. She is a postgraduate of the Department of Nuclear Science and Technology, Nanjing University of Aeronautics and Astronautics. Her research interests are in the area of radiation biology.

Ailian Wang

Ailian Wang, MD. She is a chief physician of the Department of ophthalmology, the First Affiliated Hospital, Bengbu Medical College. Her research interests are in the area of ferroptosis.

Jundong Feng

Jundong Feng, PhD. She is an associate professor of the Department of Nuclear Science and Technology, Nanjing University of Aeronautics and Astronautics. Her research interests are in the area of space radiation protection.

Xiaodan Hu

Xiaodan Hu, PhD. She is an associate professor of the Department of Nuclear Science and Technology, Nanjing University of Aeronautics and Astronautics. Her research interests are in the areas of radiation protection and degradation.

Shuquan Chang

Shuquan Chang, PhD. He is the head of the Department of Nuclear Science and Technology, Nanjing University of Aeronautics and Astronautics. His research interests are in the area of radiation protection.

Haiqian Zhang

Haiqian, Zhang, PhD. He is a professor of the Department of Nuclear Science and Technology, Nanjing University of Aeronautics and Astronautics. His research interests are in the areas of radiation biology and biodosimetry.