Usp43, a member of the deubiquitinases (DUBs) family, is crucial for removing ubiquitin from target substrates, thus regulating multiple cellular pathways. Ubiquitination of proteins governs protein degradation and fundamental cellular processes, and DUBs like Usp43 are significant regulators of pathways associated with cancer and other diseases, making Usp43 a potential therapeutic target [2].

Usp43 has been found to play diverse roles in different cancers. In bladder cancer, it stabilizes c-Myc by deubiquitinating it at specific residues, forming a positive feedback loop that promotes glycolysis and metastasis [1]. In epithelial ovarian cancer, its high expression is associated with poor prognosis, and it promotes cell proliferation, migration, invasion, and reduces cisplatin sensitivity through the HDAC2-dependent regulation of the Wnt/β-catenin signaling pathway [3]. In colorectal cancer, it promotes cell proliferation, migration, and invasion by regulating ZEB1 degradation through the ubiquitination pathway [4]. In breast cancer, it facilitates cell cycle transition, promotes EMT, and metastasis [7,8]. In cervical carcinoma, it promotes cell proliferation, migration, invasion, and EMT by activating the Hippo/TAZ pathway [5]. In ovarian serous adenocarcinoma, it promotes cell migration and invasion through epithelial-mesenchymal transition, potentially mediated by the KRAS pathway [9]. Also, it negatively regulates antiviral innate immunity by promoting TBK1 ubiquitination and degradation via the USP43/RNF2 axis [6].

In conclusion, Usp43 is a key regulator in multiple biological processes, especially in cancer-related pathways. Studies on Usp43 using various in-vitro and in-vivo models, though not specifically KO/CKO mouse models in the provided references, have revealed its role in promoting tumorigenesis, metastasis, and chemoresistance in different cancers, highlighting its potential as a therapeutic target for cancer treatment. Additionally, its role in negatively regulating antiviral innate immunity shows its importance beyond the cancer context.

References:

1. Li, Mingxing, Yu, Jingtian, Ju, Lingao, Xiao, Yu, Wang, Xinghuan. 2024. USP43 stabilizes c-Myc to promote glycolysis and metastasis in bladder cancer. In Cell death & disease, 15, 44. doi:10.1038/s41419-024-06446-7. https://pubmed.ncbi.nlm.nih.gov/38218970/

2. Zhao, Ziqi, Liu, Meichen, Lin, Zhikun, He, Hui, Tan, Guang. 2024. The mechanism of USP43 in the development of tumor: a literature review. In Aging, 16, 6613-6626. doi:10.18632/aging.205731. https://pubmed.ncbi.nlm.nih.gov/38613804/

3. Pei, Lipeng, Zhao, Feng, Zhang, Yi. 2023. USP43 impairs cisplatin sensitivity in epithelial ovarian cancer through HDAC2-dependent regulation of Wnt/β-catenin signaling pathway. In Apoptosis : an international journal on programmed cell death, 29, 210-228. doi:10.1007/s10495-023-01873-x. https://pubmed.ncbi.nlm.nih.gov/38087046/

4. Ye, Dao-Xiong, Wang, Si-Si, Huang, Ying, Wang, Xiao-Jie, Chi, Pan. 2021. USP43 directly regulates ZEB1 protein, mediating proliferation and metastasis of colorectal cancer. In Journal of Cancer, 12, 404-416. doi:10.7150/jca.48056. https://pubmed.ncbi.nlm.nih.gov/33391437/

5. Zhang, Yanhua, Liu, Yujing, Deng, Qicheng, Liu, Lifen, Zhu, Weipei. 2025. USP43 drives cervical carcinoma progression through regulation of the Hippo/TAZ pathway. In International immunopharmacology, 149, 114217. doi:10.1016/j.intimp.2025.114217. https://pubmed.ncbi.nlm.nih.gov/39922114/

6. Zhao, Xibao, Di, Qianqian, Chen, Jin, Xiao, Yue, Chen, Weilin. 2025. The USP43/RNF2 axis negatively regulates antiviral innate immunity by promoting TBK1 ubiquitination and degradation. In Cell death and differentiation, , . doi:10.1038/s41418-025-01491-x. https://pubmed.ncbi.nlm.nih.gov/40148469/

7. Lin, Fei, Xie, Zuopiao, Chang, Li, He, Wenjie, Li, Wenhui. 2017. USP43 promotes tumorigenesis through regulating cell cycle and EMT in breast cancer. In International journal of clinical and experimental pathology, 10, 11014-11021. doi:. https://pubmed.ncbi.nlm.nih.gov/31966446/

8. Xue, Ying, Li, Min, Hu, Jie, Zhang, Xiaoping, Huang, Qihong. 2022. Cav2.2-NFAT2-USP43 axis promotes invadopodia formation and breast cancer metastasis through cortactin stabilization. In Cell death & disease, 13, 812. doi:10.1038/s41419-022-05174-0. https://pubmed.ncbi.nlm.nih.gov/36137995/

9. Li, Qin, Li, Wenhao, Wang, Jiahao, Shi, Wenjing, Wang, Taorong. 2024. Effect of ubiquitin-specific proteinase 43 on ovarian serous adenocarcinoma and its clinical significance. In Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology, 44, 2361862. doi:10.1080/01443615.2024.2361862. https://pubmed.ncbi.nlm.nih.gov/38916982/