Therefore, our findings strongly suggest that USP22 plays critical oncogenic roles in the malignancy and progression of NSCLC and provide rationales for targeting USP22, which may induce broad anti-cancer activities via suppressing multiple signaling pathways including angiogenesis, EMT, c-Myc, and KRAS, as a novel therapeutic strategy for NSCLC. Here, KRAS is linked to non-small cell lung carcinoma.