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

Abstract

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.

UXT at the crossroads of cell death, immunity and neurodegenerative diseases

“…KEAP1-NRF2 signaling pathway provides new insights into the treatment of Parkinson's disease (87). Similar have been performed on lung epithelial cells and neurons in spinal cord injury (88,89). Thus, we speculate that UXT may regulate ferroptosis in cancer and neurodegenerative diseases through the P62-KEAP1-NRF2 signaling pathway.…”

Perillaldehyde mitigates ionizing radiation-induced intestinal injury by inhibiting ferroptosis via the Nrf2 signaling pathway

“…Irradiation increased the level of Nrf2 and its downstream proteins, Slc7A11 and HO-1, which possibly was the protective mechanism caused by the stress reaction. Recent studies postulate that Nrf2 is critical in alleviating lipid peroxidation and ferroptosis [24,46]. Nrf2 inhibits ferroptosis by promoting Slc7A11-mediated cystine input, GSH biosynthesis, and GPX4-mediated lipid peroxide detoxi cation.…”

“…Nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical regulator of intracellular oxidative homeostasis. Nrf2-related antioxidant stress is closely associated with ferroptosis suppression [24,25].…”

Emerging mechanisms of ferroptosis and its implications in lung cancer

“…These observations suggest that activation of the p62-KEAP1-NRF2 axis provides a theoretical basis for identifying potential treatments for RILI. [83] It is also demonstrated that the CoQ-FSP1 axis could be pharmacologically manipulated to restore RT sensitivity in KEAP1 mutant or de cient lung cancers. [38] Moreover, inhibition of RBMS1 activity by knocking down RBMS1 or using nortriptyline hydrochloride (NTP) can restore the radiosensitivity of lung cancer cells to some extent.…”

“…These observations suggest that activation of the p62–KEAP1–NRF2 axis provides a theoretical basis for identifying potential treatments for RILI. [83]…”