Activation of The P62-Keap1-NRF2 Pathway Protects Against Ferroptosis in Radiation-Induced Lung Injury

Abstract

Background Radiation-induced lung injury (RILI) is one of the most common, serious and dose-limiting complications of thoracic radiotherapy. A primary reason 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 induced by irradiation might be the original trigger of ferroptosis in RILI. Furthermore, activation of the P62-Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (NRF2) pathway has been shown to exert a protective effect, blunting ferroptosis. Therefore, this study aims to explore the protective effect of the P62-Keap1-NRF2 pathway against radiation-induced ferroptosis in alveolar epithelial cells. Results Firstly, our results demonstrated that radiation induced ferroptosis in vitro RILI cell model, which could be significantly reduced by Ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis. Then, we found that overexpression of P62 interacted with Keap1 to promote NRF2 translocation into the nucleus and upregulation its target proteins quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO1) and ferritin heavy chain 1 (FTH1). Conclusion Collectively, the activation of the P62-Keap1-NRF2 pathway prevents radiation-induced ferroptosis in RILI cells, providing a theoretical basis for further research to find a potential approach for RILI therapy.