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

作者：Xiaoying Qian, Yong Wang, Peng Kuang, Bingda Li, Ke Jiang, Anqi Wang, Kangping Xiong, Weiwei Hong, Biao Yu, Guizhen Qin, Xinyuan Yao, Xin Ye, Chunli Luo, Chengsi Shu, Dengying Chen, Wenhao Zheng, Xiangzhi Chai, Yinan Sun, Zhaoqing Li, Yong Li · 发表于：Redox Biology · 年份：2026 · DOI：10.1016/j.redox.2026.104091 · 被引用次数：5 · 研究领域：Ferroptosis and cancer prognosis、Cancer-related molecular mechanisms research、Effects of Radiation Exposure

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 suppresse...