NVP-AUY922 alleviates radiation-induced lung injury via inhibition of autophagy-dependent ferroptosis

Li Li,Jin Li,Dongming Wu,Ting Zhang,Ying Xu,Feng Zhang,Shihua Deng,Ye Zou

doi:10.1038/s41420-022-00887-9

Abstract

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.

Highlights

Radiotherapy is a momentous and commonly used therapeutic modality for various tumors [1, 2]
Lung injury is strongly associated with a poor prognosis in patients treated with radiotherapy [33]
Lung inflammation plays a pivotal role in Radiation-induced lung injury (RILI) and can directly or indirectly cause damage to the microvascular endothelium and alveolar epithelium in the lung, which are the primary sources of RILI pathogenesis, and a heavy burden on critically ill patients [34]

Summary

Introduction

Radiotherapy is a momentous and commonly used therapeutic modality for various tumors [1, 2]. Radiation-induced lung injury (RILI) occurs during the early stages of radiotherapy and is one of the independent risk factors for radiation-induced death [3]. Some traditional radioprotective drugs have a protective effect on normal lung tissue, they weaken the sensitivity of tumor cells to radiation. These radioprotective drugs greatly reduce the effect of tumor radiotherapy, restricting their application in chest radiotherapy for clinical tumor patients [6]. A new radioprotective drug with significant curative effects, low toxicity, and side effects is necessary for the clinical treatment of RILI

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Results

Conclusion