Our findings address a critical gap in understanding STAT3 deubiquitination in CRC by identifying USP5 as a novel DUB for STAT3 and demonstrating its oncogenic role in CRC progression, and highlight the potential of the USP5/STAT3 axis as a therapeutic target for CRC for the first time, indicating that strategically promoting STAT3 degradation by inhibiting USP5 may be a promising approach for CRC prevention and treatment. The gene discussed is USP5; the disease is colorectal carcinoma.