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.