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

作者：Hui Feng, Qijuan Wang, Liu Li, Lihuiping Tao, Shuhong Zeng, Ziwen Li, Minmin Fan, Chengtao Yu, Dongdong Sun, Weixing Shen, Haibo Cheng · 发表于：International Journal of Biological Sciences · 年份：2025 · DOI：10.7150/ijbs.119868 · 被引用次数：3 · 研究领域：Ubiquitin and proteasome pathways、Cytokine Signaling Pathways and Interactions、NF-κB Signaling Pathways

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.