Usp11, a member of the ubiquitin-specific protease family, is a deubiquitinating enzyme (DUB) involved in various biological processes. It plays a role in regulating cell cycle, DNA repair, signaling pathways, and is associated with tumor development [6]. It participates in pathways such as those related to ferroptosis, autophagy, and multiple cancer-related signaling cascades. Genetic models, like gene knockout mouse models, have been crucial in studying its functions.

In spinal cord ischemia-reperfusion injury, knockout of Usp11 (Usp11-/Y) decreased neuronal cell ferroptosis and promoted functional recovery, indicating Usp11's role in regulating autophagy-dependent ferroptosis [1]. In intervertebral disc degeneration, Usp11-/-mice showed exacerbated disease and poor pain-related behavioral scores, while overexpression of Usp11 ameliorated oxidative stress-induced ferroptosis by stabilizing Sirt3 [2]. In hepatocellular carcinoma, Usp11 promotes metastasis via the eEF1A1/SP1/HGF axis, and its knockdown could potentially disrupt this metastatic process [3]. In radiation-induced pneumonitis, Usp11-/-mice had alleviated disease progression, with reduced pro-inflammatory cytokine expression and decreased pulmonary vessel permeability [4]. In colorectal cancer, knockdown of Usp11 may increase cell sensitivity to ferroptosis as it stabilizes LSH through deubiquitination [5]. In prostate cancer, Usp11 knockdown significantly inhibited cell growth by down-regulating AR and c-Myc activities [7].

In conclusion, Usp11 has diverse and significant functions in regulating biological processes related to ferroptosis, autophagy, and cancer development. The use of Usp11 knockout mouse models has provided valuable insights into its role in diseases such as spinal cord ischemia-reperfusion injury, intervertebral disc degeneration, various cancers, and radiation-induced pneumonitis, potentially guiding the development of targeted therapies.

References:

1. Rong, Yuluo, Fan, Jin, Ji, Chengyue, Cai, Weihua, Liu, Wei. 2021. USP11 regulates autophagy-dependent ferroptosis after spinal cord ischemia-reperfusion injury by deubiquitinating Beclin 1. In Cell death and differentiation, 29, 1164-1175. doi:10.1038/s41418-021-00907-8. https://pubmed.ncbi.nlm.nih.gov/34839355/

2. Zhu, Jian, Sun, Ruping, Sun, Kaiqiang, Kong, Fanqi, Shi, Jiangang. 2023. The deubiquitinase USP11 ameliorates intervertebral disc degeneration by regulating oxidative stress-induced ferroptosis via deubiquitinating and stabilizing Sirt3. In Redox biology, 62, 102707. doi:10.1016/j.redox.2023.102707. https://pubmed.ncbi.nlm.nih.gov/37099926/

3. Chen, Jin, Ning, Deng, Du, Pengcheng, Zhang, Bixiang, Chen, Xiaoping. 2023. USP11 potentiates HGF/AKT signaling and drives metastasis in hepatocellular carcinoma. In Oncogene, 43, 123-135. doi:10.1038/s41388-023-02847-8. https://pubmed.ncbi.nlm.nih.gov/37973952/

4. Tang, Yiting, Wang, Tingya, Gu, Liming, Cao, Jianping, Jiao, Yang. 2024. USP11 Exacerbates Radiation-Induced Pneumonitis by Activating Endothelial Cell Inflammatory Response via OTUD5-STING Signaling. In International journal of radiation oncology, biology, physics, 119, 1261-1274. doi:10.1016/j.ijrobp.2024.01.220. https://pubmed.ncbi.nlm.nih.gov/38364946/

5. Duan, Junyi, Huang, Daoyuan, Liu, Cheng, Wang, Weiping, Shao, Genze. 2023. USP11-mediated LSH deubiquitination inhibits ferroptosis in colorectal cancer through epigenetic activation of CYP24A1. In Cell death & disease, 14, 402. doi:10.1038/s41419-023-05915-9. https://pubmed.ncbi.nlm.nih.gov/37414755/

6. Guo, Tuanjie, Tang, Heting, Yuan, Zhihao, Zhang, Encheng, Wang, Xiang. 2022. The Dual Role of USP11 in Cancer. In Journal of oncology, 2022, 9963905. doi:10.1155/2022/9963905. https://pubmed.ncbi.nlm.nih.gov/35359344/

7. Pornour, Majid, Jeon, Hee-Young, Ryu, Hyunju, Barbieri, Christopher, Qi, Jianfei. 2024. USP11 promotes prostate cancer progression by up-regulating AR and c-Myc activity. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2403331121. doi:10.1073/pnas.2403331121. https://pubmed.ncbi.nlm.nih.gov/39052835/