Lung cancer is one of the most malignant and prevalent tumors and accounts for the vast majority of cancer death worldwide. However, the molecular mechanisms underlying lung cancer progression are poorly understood. Here, we reveal that both transcription and protein expression levels of Cox15 were increased in lung cancer. Nrf2 specifically binds to the Cox15 promoter and triggers Cox15 expression at the transcriptional level. Cox15 functions as a novel oncogene that facilitates lung cancer cell proliferation. Additionally, Aripiprazole, a potent inhibitor of Cox15, executives profoundly suppressive effects on lung cancers cells growth and tumor progression in vivo and in vitro through exerting therapeutic effects. Taken together, our results unravel that Cox15 holds great potential to act as a prognostic molecule for lung cancer patients' prognosis in the future.Copyright © 2021. Published by Elsevier Inc.