USP25, a ubiquitin-specific peptidase, is a key member of the deubiquitinating enzyme family. It plays crucial roles in various biological processes by precisely controlling protein function, localization, and degradation, thus being involved in multiple pathways such as the Wnt/β -catenin, NF -κB, and MAPK signaling pathways [1,2,4,8,9].

In pathological cardiac hypertrophy, USP25 deficiency aggravated cardiac hypertrophy and dysfunction as it binds to and deubiquitinates SERCA2a, a protein that counteracts hypertrophy, to maintain its stability [1]. In cerebral ischemic stroke, USP25 -deficient mice had more severe injury, indicating its role in inhibiting microglia -mediated neuroinflammation [2]. In Alzheimer's disease, genetic deletion of Usp25 reduced amyloid deposition, suggesting it promotes amyloid pathology [3]. In hepatocellular carcinoma, USP25 knockdown in cells and gene deletion in mouse models decreased tumor cell proliferation, migration, and invasion, showing its role in promoting cancer progression [4]. In male mice with acetaminophen -induced liver injury, inactivation of Usp25, either genetically or pharmacologically, attenuated liver injury [5]. Usp25 knockout mice showed increased seizure susceptibility, indicating its potential role in epilepsy [6]. In colon cancer, USP25 deficiency impaired DNA repair and sensitized cells to chemotherapy [7]. In diabetic nephropathy, ablation of USP25 in mice exacerbated renal dysfunction and fibrosis [8]. In acute pancreatitis, Usp25 deficiency in macrophages of mice exacerbated pancreatic and lung injury [9]. In IgG4 -related disease, reduced USP25 expression in mice led to increased fibrosis and inflammation [10].

In summary, USP25 plays diverse and significant roles in multiple biological processes and diseases. Gene knockout mouse models have been instrumental in revealing its functions, such as in cardiac, neurological, and various disease -related contexts, highlighting its potential as a therapeutic target in these areas.

References:

1. Ye, Bozhi, Zhou, Hao, Chen, Yanghao, Wang, Xu, Liang, Guang. 2023. USP25 Ameliorates Pathological Cardiac Hypertrophy by Stabilizing SERCA2a in Cardiomyocytes. In Circulation research, 132, 465-480. doi:10.1161/CIRCRESAHA.122.321849. https://pubmed.ncbi.nlm.nih.gov/36722348/

2. Li, Zhongding, Liu, Baohua, Lambertsen, Kate Lykke, Song, Weihong, Wang, Xu. 2023. USP25 Inhibits Neuroinflammatory Responses After Cerebral Ischemic Stroke by Deubiquitinating TAB2. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2301641. doi:10.1002/advs.202301641. https://pubmed.ncbi.nlm.nih.gov/37587766/

3. Zheng, Qiuyang, Song, Beibei, Li, Guilin, Song, Weihong, Wang, Xin. . USP25 inhibition ameliorates Alzheimer's pathology through the regulation of APP processing and Aβ generation. In The Journal of clinical investigation, 132, . doi:10.1172/JCI152170. https://pubmed.ncbi.nlm.nih.gov/35229730/

4. Liu, Yinghui, Ma, Jingjing, Lu, Shimin, He, Pengzhan, Dong, Weiguo. 2023. USP25 promotes hepatocellular carcinoma progression by interacting with TRIM21 via the Wnt/β-catenin signaling pathway. In Chinese medical journal, 136, 2229-2242. doi:10.1097/CM9.0000000000002714. https://pubmed.ncbi.nlm.nih.gov/37439386/

5. Cai, Changzhou, Ma, Huailu, Peng, Jin, Ji, Feng, Wang, Jiewei. 2023. USP25 regulates KEAP1-NRF2 anti-oxidation axis and its inactivation protects acetaminophen-induced liver injury in male mice. In Nature communications, 14, 3648. doi:10.1038/s41467-023-39412-6. https://pubmed.ncbi.nlm.nih.gov/37339955/

6. Fan, Cui-Xia, Liu, Xiao-Rong, Mei, Dao-Qi, Chen, Qian, Shi, Yi-Wu. . Heterozygous variants in USP25 cause genetic generalized epilepsy. In Brain : a journal of neurology, 147, 3442-3457. doi:10.1093/brain/awae191. https://pubmed.ncbi.nlm.nih.gov/38875478/

7. Li, Yunhui, Li, Lei, Wang, Xinshu, Lou, Zhenkun, Yuan, Jian. 2024. USP25 Elevates SHLD2-Mediated DNA Double-Strand Break Repair and Regulates Chemoresponse in Cancer. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2403485. doi:10.1002/advs.202403485. https://pubmed.ncbi.nlm.nih.gov/38803048/

8. Liu, Baohua, Miao, Xiaomin, Shen, Jiangyun, Song, Weihong, Wang, Xu. 2023. USP25 ameliorates diabetic nephropathy by inhibiting TRAF6-mediated inflammatory responses. In International immunopharmacology, 124, 110877. doi:10.1016/j.intimp.2023.110877. https://pubmed.ncbi.nlm.nih.gov/37657242/

9. Liu, Xin, Luo, Wu, Chen, Jiahao, Liang, Guang, Wang, Yi. 2022. USP25 Deficiency Exacerbates Acute Pancreatitis via Up-Regulating TBK1-NF-κB Signaling in Macrophages. In Cellular and molecular gastroenterology and hepatology, 14, 1103-1122. doi:10.1016/j.jcmgh.2022.07.013. https://pubmed.ncbi.nlm.nih.gov/35934222/

10. Jiang, Panpan, Jing, Yukai, Zhao, Siyu, Dong, Lingli, Liu, Chaohong. 2024. Expression of USP25 associates with fibrosis, inflammation and metabolism changes in IgG4-related disease. In Nature communications, 15, 2627. doi:10.1038/s41467-024-45977-7. https://pubmed.ncbi.nlm.nih.gov/38521787/