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

## TL;DR

α-hederin fights colorectal cancer by targeting USP5 and disrupting STAT3 deubiquitination, a key process in tumor growth.

## Contribution

Identifies USP5 as a novel deubiquitinating enzyme of STAT3 and shows α-hederin's anti-tumor mechanism in colorectal cancer.

## Key findings

- α-hederin directly targets and reduces USP5 expression.
- USP5 deubiquitinates STAT3, promoting colorectal cancer progression.
- Disrupting USP5-mediated STAT3 deubiquitination inhibits tumorigenesis.

## Abstract

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.