Ionizing radiation promotes lung injury by inducing ferroptosis-driven senescence in epithelial cells via NCOA4-mediated ferritinophagy.

Radiation-induced lung injury (RILI) is a dose-limiting factor in thoracic radiotherapy, and effective treatments are currently lacking. Ionizing radiation (IR) induced senescence of lung epithelial cells is considered a central process in the development and progression of RILI. Ferroptosis, a form of regulated cell death characterized by iron dependency, has been implicated in various IR-induced injuries, including RILI. However, whether ferroptosis participates in the pathological process of cellular senescence remains unreported. In this study, we investigated the potential association between ferroptosis and senescence in lung epithelial cells during RILI, as well as the upstream regulatory mechanisms. Our research found that IR induces mitochondrial dysfunction and senescence in lung epithelial cells and promotes the release of the senescence-associated secretory phenotype (SASP). These effects can be effectively inhibited by the ferroptosis inhibitor Ferrostatin-1 (Fer-1). Further study revealed that IR-induced iron overload and ferroptosis are closely associated with ferritin degradation. Inhibition of autophagy with 3-methyladenine (3-MA) reduced ferritin heavy chain (FTH) degradation, thereby alleviating IR-induced ferroptosis and cellular senescence, suggesting that ferritinophagy is involved in these processes. Additionally, in vivo and in vitro experiments demonstrated that IR activates nuclear receptor coactivator 4 (NCOA4). Knockdown of NCOA4 in vitro suppressed iron overload and ferroptosis in lung epithelial cells and ameliorated cellular senescence. In vivo administration of compound 9a disrupts the NCOA4-FTH interaction, thereby inhibiting NCOA4-mediated ferritinophagy. This inhibition reduced intracellular iron levels and ferroptosis, improved mitochondrial function and epithelial cell senescence, and ultimately mitigated RILI. These findings indicate ferroptosis as a key regulator of IR-induced senescence in lung epithelial cells and highlight the critical role of NCOA4-mediated ferritinophagy in the pathogenesis of RILI.