The key findings of the study are as follows: (i) USP22 enhances CRC cell migration and invasion by inducing EMT, (ii) USP22 directly increases AP4 transcription to induce EMT and promote CRC cell metastasis to the lungs in vivo, and (iii) USP22 and AP4 overexpression is related to CRC progression and liver metastasis and poor outcomes in CRC patients. Here, USP22 is linked to colorectal carcinoma.