PSMA6 drives non-small cell lung cancer progression by stabilizing NEDD8 and activating NF-κB signaling.

Background: Non‑small cell lung cancer (NSCLC) is a major cause of cancer‑associated death globally. Elucidating novel molecular drivers is essential for targeted therapy development. This study sought to investigate the function and regulatory mechanism of proteasome 20S subunit alpha 6 (PSMA6) in NSCLC. Methods: Proteasome 20S subunit alpha 6 (PSMA6) expression in NSCLC tissues and cells was analyzed using The Cancer Genome Atlas (TCGA) datasets, immunohistochemistry, and Western blotting. Gain- and loss-of-function assays were performed to evaluate its biological functions. Protein interaction assays and functional rescue experiments were conducted to investigate the underlying mechanisms. Results: We found that PSMA6 was significantly upregulated in NSCLC tissues and cell lines and was associated with poor patient prognosis. Functional experiments demonstrated that PSMA6 promoted NSCLC cell proliferation and migration. Mechanistically, PSMA6 activated nuclear factor kappa B (NF-κB) signaling by enhancing p65 nuclear translocation and IκBα phosphorylation. Further investigation revealed that PSMA6 directly interacted with neural precursor cell expressed, developmentally down-regulated 8 (NEDD8) and increased its protein stability without affecting its mRNA level. Importantly, NEDD8 knockdown abolished PSMA6-induced NF-κB activation and malignant phenotypes, confirming that PSMA6 exerts its oncogenic effects through the NEDD8/NF-κB axis. Conclusions: Our findings identify a novel PSMA6/NEDD8/NF-κB regulatory axis that promotes NSCLC progression and suggest PSMA6 as a potential therapeutic target.