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.

中文翻译：

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铁他汀-1对小鼠造血急性辐射综合征的造血保护作用及机制

 抽象的

 目的

最近报道黄芩素（一种抗铁死亡药物）在与抗细胞凋亡和抗坏死性凋亡药物高剂量全身照射后可协同提高小鼠的存活率。同时，我们课题组还证明，铁死亡抑制剂 Ferrostatin-1 可将造血急性放射综合征小鼠模型的存活率提高至 60%，持续 150 天 ( p < .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 减轻辐射诱导的铁死亡和随后的造血急性辐射综合征的机制。

 材料和方法

雄性 ICR 小鼠（8-10 周龄）暴露于¹³⁷ Cs 源发出的 0、8 或 10 Gy 剂量的辐射。照射后 72 小时将 Ferrostatin-1 腹腔注射到小鼠体内。对骨髓单个核细胞（BMMC）和外周血细胞进行计数。采用生化或免疫学方法评估铁相关参数、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。抗体技术。

 结果

Ferrostatin-1 通过减轻 BMMC 的铁死亡，增加了小鼠全身照射后外周血中红细胞、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并消耗酰基辅酶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和谷胱甘肽水平来诱导BMMCs铁死亡。铁死亡的 BMMC 在辐射暴露的早期阶段不释放 TNF-α、IL-6 或 IL-1β。 Ferrostatin-1 通过减弱含铁血黄素和易感铁池水平的增加以及 ASCL4 和谷胱甘肽过氧化物酶 4 水平的降低来减轻辐射诱导的铁死亡的脂质过氧化。

 结论

全身辐射诱导的 BMMC 铁死亡涉及铁、脂质代谢酶和抗脂质过氧化分子的变化。 Ferrostatin-1 通过作用于这些目标，可能成为一种潜在的辐射缓解剂。