These results showed that USP5 was significantly upregulated during CRC progression and played a critical role in stabilizing STAT3 protein, whereas α-hederin impeded the development of CRC by directly targeting USP5, an oncoprotein, and inhibited USP5 expression as well as weakened its interaction with STAT3, thereby disrupting STAT3 protein stability mediated by USP5 and increased the level of STAT3 ubiquitination. Here, STAT3 is linked to colorectal carcinoma.