This study underscores the key role of SETDB1-mediated Akt K64 methylation, which serves as a poor prognosis marker in non-small cell lung cancer (NSCLC) patients, in driving Akt ubiquitination and hyperactivation for promoting cancer progression, hence representing a novel paradigm for targeting NSCLC. This evidence concerns the gene SETDB1 and non-small cell lung carcinoma.