Li Li, Wu Dongming, Deng Shihua, Li Jin, Zhang Feng, Zou Ye, Zhang Ting, Xu Ying
School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, 610500, P.R. China.
The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, 610500, P.R. China.
Cell Death Discov. 2022 Feb 26;8(1):86. doi: 10.1038/s41420-022-00887-9.
Radiation-induced lung injury (RILI) is a common complication of radiotherapy for which no effective interventions are available. NVP-AUY922, a resorcinylic isoxazole amide drug, exhibits anti-inflammatory, immunomodulatory, and therapeutic effects against various types of cancers. In this study, we explore the role and underlying mechanisms of NVP-AUY922 in the treatment of RILI. We established a model of BEAS-2B cell injury and a mouse model of RILI. Cell proliferation, death, gross weight, and survival rates of mice, and histological parameters were assessed. Additionally, inflammation-related indices and indicators related to ferroptosis were evaluated. Furthermore, immunofluorescence and co-immunoprecipitation were used to determine the interaction between GPX4, LAMP-2A, and HSC70. NVP-AUY922 significantly ameliorated radiation-induced lung tissue damage, inflammatory cell infiltration, proinflammatory cytokine release, and lung epithelial BEAS-2B cell damage. NVP-AUY922 markedly limited the activation of ferroptosis, which is involved in RILI. Mechanistically, NVP-AUY922 prevented chaperone-mediated autophagy of the GPX4 pathway in vitro and in vivo, and the autophagy inhibitor Baf-A1 significantly increased the level of GPX4 and alleviated lung inflammation. NVP-AUY922 can alleviate RILI by inhibiting chaperone-mediated lysosomal degradation of GPX4, demonstrating its potential as a novel protective agent against RILI.
放射性肺损伤（RILI）是放射治疗的常见并发症，目前尚无有效的干预措施。NVP-AUY922是一种间苯二酚异恶唑酰胺类药物，对多种癌症具有抗炎、免疫调节和治疗作用。在本研究中，我们探讨了NVP-AUY922在治疗RILI中的作用及潜在机制。我们建立了BEAS-2B细胞损伤模型和RILI小鼠模型。评估了细胞增殖、死亡、小鼠体重和存活率以及组织学参数。此外，还评估了炎症相关指标和与铁死亡相关的指标。此外，采用免疫荧光和免疫共沉淀法确定GPX4、LAMP-2A和HSC70之间的相互作用。NVP-AUY922显著改善了辐射诱导的肺组织损伤、炎性细胞浸润、促炎细胞因子释放和肺上皮BEAS-2B细胞损伤。NVP-AUY922明显限制了参与RILI的铁死亡的激活。机制上，NVP-AUY922在体外和体内均阻止了GPX4途径的伴侣介导的自噬，自噬抑制剂Baf-A1显著提高了GPX4水平并减轻了肺部炎症。NVP-AUY922可通过抑制伴侣介导的GPX4溶酶体降解来减轻RILI，证明其作为一种新型RILI保护剂的潜力。
