NEDD4-Mediated Endothelial-Mesenchymal Transition Participates in Radiation-Induced Lung Injury Through the ATM Signaling Pathway.

OBJECTIVE

To elucidate the role of NEDD4 in ionizing radiation (IR)-induced endothelial-mesenchymal transition (EndMT) and its molecular mechanism in radiation-induced lung injury (RILI), given the unclear regulatory pathways of EndMT in RILI pathogenesis.

METHODS

IR-induced EndMT was observed during RILI in vivo and in vitro by immunohistochemical staining and Western blot analysis. Proteomics identified NEDD4 as a candidate, validated by RNA sequencing (RNA-seq) and quantitative real-time polymerase chain reaction (qRT‒PCR). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis linked NEDD4 to PI3K-AKT signaling. Co-immunoprecipitation (Co-IP) confirmed NEDD4-ATM interaction.

RESULTS

IR upregulated NEDD4 in endothelial cells, correlating with EndMT progression. NEDD4 overexpression enhanced ATM pathway activation, modulating genes upstream/downstream of ATM. Co-IP verified physical NEDD4-ATM binding, suggesting NEDD4 stabilizes ATM to promote EndMT.

CONCLUSION

Overall, our study shows that NEDD4 mediates EndMT to participate in RILI through the ATM signaling pathway, which may break new ground for understanding the occurrence and development of RILI.