Abstract

Radiotherapy resistance (RT resistance) remains a major obstacle in lung adenocarcinoma (LUAD) treatment, with dysregulated apoptosis being a key contributor. This study aim to investigate the role of PDPK1 in RT resistance in LUAD and its molecular mechanism. RT-resistant sublines (A549R/PC9R) were established via fractionated irradiation. Bioinformatic analysis (GSE197236 dataset) was performed to identify differentially expressed genes (DEGs). RNA sequencing, qPCR, ChIP, and dual-luciferase assays were conducted to elucidate the underlying mechanism. Cell viability, colony formation, and apoptosis were performed to functional validation. Results showed that PDPK1 was significantly upregulated in RT-resistant cells. PDPK1 knockdown inhibited cell viability and colony formation while promoting apoptosis in A549R and PC9R cells. Mechanistically, PDPK1 activated NFKB1, which in turn transactivated BIRC3, a key anti-apoptotic protein. BIRC3 overexpression reversed the pro-apoptotic effects of PDPK1 knockdown, restoring cell survival. These findings establish the PDPK1/NFKB1/BIRC3 signaling axis as a critical driver of RT resistance in NSCLC. In conclusion, our study reveals a novel molecular mechanism by which PDPK1 mediates RT resistance through the NFKB1/BIRC3 axis. Targeting this signaling pathway may represent a promising strategy to overcome RT resistance in LUAD.