Department of Nuclear Science and Technology, College of Materials Science and Technology, Nanjing University of Aeronautics and Astronautics, Nanjing City, P. R. China.
Jiangsu Key Laboratory for Biomaterials and Devices, Southeast University, Nanjing City, P. R. China.
Int J Radiat Biol. 2021;97(4):464-473. doi: 10.1080/09553002.2021.1876956. Epub 2021 Jan 31.
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 ( < .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.
Male ICR mice (8-10 weeks old) were exposed to doses of 0, 8, or 10 Gy irradiated from a Cs 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.
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.
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.
最近有报道称，白杨素（一种抗铁死亡药物）与抗细胞凋亡和抗细胞坏死药物联合使用，可显著提高大剂量全身照射后小鼠的存活率。同时，我们的研究小组已经证明，铁死亡抑制剂 ferrostatin-1 可将造血急性辐射综合征小鼠模型的存活率提高至 150 天的 60%（<0.001）。这些现象表明，铁死亡抑制可以减轻辐射损伤。在本研究中，我们继续研究 ferrostatin-1 缓解辐射诱导的铁死亡和随后的造血急性辐射综合征的机制。
雄性 ICR 小鼠（8-10 周龄）接受 0、8 或 10Gy 的 Cs 源照射。辐射后 72 小时，通过腹腔注射 ferrostatin-1。计数骨髓单个核细胞（BMMCs）和外周血细胞。采用生化或抗体技术检测铁相关参数、脂质代谢酶、脂质过氧化修复分子（谷胱甘肽过氧化物酶 4、谷胱甘肽和辅酶 Q10）和炎症因子（TNF-α、IL-6 和 IL-1β）的变化。
ferrostatin-1 通过减轻 BMMC 铁死亡，增加全身照射后小鼠外周血中红细胞、白细胞、淋巴细胞和单核细胞的数量。全身照射通过增加铁和脂质过氧化水平以及耗竭酰基辅酶 A 合成酶长链家族成员 4（ASCL4）、脂氧合酶 15、谷胱甘肽过氧化物酶 4 和谷胱甘肽水平，诱导 BMMC 发生铁死亡。在辐射暴露的早期，铁死亡的 BMMC 并未释放 TNF-α、IL-6 或 IL-1β。Ferrostatin-1 通过减轻血红素和易铁池水平的升高以及 ASCL4 和谷胱甘肽过氧化物酶 4 水平的降低，缓解了辐射诱导的铁死亡的脂质过氧化。
BMMC 中全身照射诱导的铁死亡的发生涉及铁、脂质代谢酶和抗脂质过氧化分子的变化。Ferrostatin-1 可以通过作用于这些靶点成为一种有潜力的辐射缓解剂。
