<br>P62-Keap1-NRF2 通路的激活可防止辐射引起的肺损伤中的铁死亡,Oxidative Medicine and Cellular Longevity

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P62-Keap1-NRF2 通路的激活可防止辐射引起的肺损伤中的铁死亡
Oxidative Medicine and Cellular Longevity Pub Date : 2022-07-05 , DOI: 10.1155/2022/8973509
Xuan Li ₁ , Jingyao Chen ₂ , Sujuan Yuan ₁ , Xibing Zhuang ₁ , Tiankui Qiao ₁

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放射性肺损伤（RILI）是胸部放疗最常见、最严重、剂量限制性毒性之一。造成这种情况的主要原因是辐射引起的细胞死亡。铁死亡是最近公认的一种受调节的细胞死亡形式，其特征是脂质过氧化产物和致命活性氧（ROS）的积累。辐射产生的ROS可能是RILI中铁死亡的原始触发因素。此外，P62-Kelch 样 ECH 相关蛋白 1 (Keap1)-核因子红细胞 2 相关因子 2 (NRF2) 通路的激活已被证明可以减弱铁死亡，从而起到保护因子的作用。因此，本研究旨在探讨P62-Keap1-NRF2通路对辐射诱导的肺泡上皮细胞铁死亡的保护作用。首先，我们使用 RILI 细胞模型在体外发现辐射诱导的铁死亡，这种情况可以被一种特定的铁死亡抑制剂 ferostatin-1 (Fer-1) 显着减少。此外，P62的过表达与Keap1相互作用，促进NRF2易位到细胞核中并促进其靶蛋白的表达，包括醌氧化还原酶1（NQO1）、血红素加氧酶1（HO1）和铁蛋白重链1（FTH1）。总之，我们的结果表明，P62-Keap1-NRF2 通路的激活可防止 RILI 细胞中辐射诱导的铁死亡，为寻找 RILI 的潜在治疗方法提供理论基础。

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Activation of the P62-Keap1-NRF2 Pathway Protects against Ferroptosis in Radiation-Induced Lung Injury

Radiation-induced lung injury (RILI) is one of the most common, serious, and dose-limiting toxicities of thoracic radiotherapy. A primary cause for this is the radiation-induced cell death. Ferroptosis is a recently recognized form of regulated cell death, characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS). The ROS generated by irradiation might be the original trigger of ferroptosis in RILI. In addition, activation of the P62-Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (NRF2) pathway has been shown to blunt ferroptosis and thus acts as a protective factor. Therefore, this study aimed to explore the protective effect of the P62-Keap1-NRF2 pathway against radiation-induced ferroptosis in alveolar epithelial cells. First, we found that radiation induced ferroptosis in vitro using a RILI cell model, which could be significantly reduced by ferrostatin-1 (Fer-1), a specific ferroptosis inhibitor. Additionally, overexpression of P62 interacted with Keap1 to facilitate the translocation of NRF2 into the nucleus and promote the expression of its target proteins, including quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO1), and ferritin heavy chain 1 (FTH1). In summary, our results demonstrated that the activation of the P62-Keap1-NRF2 pathway prevents radiation-induced ferroptosis in RILI cells, providing a theoretical basis of finding a potential therapeutic approach for RILI.

更新日期：2022-07-05

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