α-hederin Targets USP5 to Inhibit Colorectal Tumorigenesis by Disrupting STAT3 Deubiquitination

α-hederin is a natural compound that is used to treat colorectal cancer (CRC). However, the precise anti-CRC mechanism needs to be explored further, and its direct targets have not yet been reported. In the present study, for the first time, we revealed that α-hederin directly targeted ubiquitin specific peptidase 5 (USP5), decreased its expression, weakened its interaction with signal transducer and activator of transcription 3 (STAT3), and disrupted STAT3 deubiquitination, thereby inhibiting colorectal tumorigenesis. This is particularly significant because STAT3 is a key mediator of inflammation and tumorigenesis, and targeting STAT3 deubiquitination represents a promising pathway for combating CRC; however, its deubiquitination mechanism in CRC remains unclear. USP5, a deubiquitinating enzyme (DUB) involved in inflammatory responses that is highly expressed in primary CRC tissues and promotes tumorigenesis by stabilizing tumor proteins, was identified in our study as a novel DUB of STAT3. In addition, we showed that USP5 serves as an oncogene in CRC by deubiquitinating STAT3, which contributes to CRC progression. Overall, our study provided evidence that α-hederin exhibits significant potential in suppressing colorectal tumorigenesis by disrupting USP5-mediated STAT3 deubiquitination.