USP48, also formerly known as USP31, is a deubiquitinating enzyme belonging to the ubiquitin-specific protease family. It plays crucial roles in various biological processes by regulating protein stability through deubiquitination. It is involved in pathways such as NF-κB signaling and is important for processes like synapse remodeling, pyroptosis, and cancer-related events [4].

In cancer research, loss-of-function experiments have provided valuable insights. In a CRISPR-Cas9 screen, loss of USP48 significantly inhibited cell pyroptosis, indicating its role in promoting this form of programmed cell death by stabilizing gasdermin E (GSDME) [1]. In ovarian cancer, USP48 knockdown inhibited cell migration, invasion, and increased apoptosis after carboplatin treatment, suggesting it sustains chemoresistance and metastasis [3]. In colorectal cancer, blockade of USP48 promoted degradation of oncogenic HMGA2, suppressing tumor invasion and metastasis [2]. However, another study showed that USP48 expression was downregulated in CRC, and it inhibited CRC progression by stabilizing TAK1 and promoting M1-like macrophage polarization [6]. In a mouse model of bone cancer pain, reducing spinal cord level USP48 expression was associated with pain, and its overexpression alleviated pain by antagonizing ubiquitin-mediated autophagic degradation of MrgC [5].

In conclusion, USP48 is a significant deubiquitinating enzyme involved in multiple biological processes. Through gene knockout or knockdown studies in mouse models, its roles in cancer (such as pyroptosis regulation, chemoresistance, and metastasis), and in bone cancer pain have been revealed. These findings contribute to understanding disease mechanisms and suggest USP48 could be a potential therapeutic target in these disease areas.

References:

1. Ren, Yidan, Feng, Maoxiao, Hao, Xiaodong, Wang, Qin, Wang, Yunshan. . USP48 Stabilizes Gasdermin E to Promote Pyroptosis in Cancer. In Cancer research, 83, 1074-1093. doi:10.1158/0008-5472.CAN-22-1812. https://pubmed.ncbi.nlm.nih.gov/36607699/

2. Cheng, Can, Yao, Hanhui, Li, Heng, Fang, Zhengdong, Wu, Liang. 2024. Blockade of the deubiquitinating enzyme USP48 degrades oncogenic HMGA2 and inhibits colorectal cancer invasion and metastasis. In Acta pharmaceutica Sinica. B, 14, 1624-1643. doi:10.1016/j.apsb.2024.01.006. https://pubmed.ncbi.nlm.nih.gov/38572092/

3. Lei, Xuemeng, Li, Xukun, Chen, Hongyan, Liu, Zhihua. . USP48 Sustains Chemoresistance and Metastasis in Ovarian Cancer. In Current cancer drug targets, 20, 689-699. doi:10.2174/1568009620666200503045400. https://pubmed.ncbi.nlm.nih.gov/32359336/

4. Ma, Qi, Ruan, Hongyu, Dai, Huihui, Yao, Wei-Dong. 2023. USP48/USP31 Is a Nuclear Deubiquitinase that Potently Regulates Synapse Remodeling. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.09.19.558317. https://pubmed.ncbi.nlm.nih.gov/37781625/

5. Yu, Jiacheng, Hou, Bailing, Huang, Yulin, Ma, Zhengliang, Sun, Yue. 2023. USP48 alleviates bone cancer pain and regulates MrgC stabilization in spinal cord neurons of male mice. In European journal of pain (London, England), 27, 723-734. doi:10.1002/ejp.2102. https://pubmed.ncbi.nlm.nih.gov/36864656/

6. Zhang, Xinwen, Zhao, Jiawei, Qi, Guangying, Wang, Zhenran, Jin, Jiamin. 2025. USP48 inhibits colorectal cancer progression and promotes M1-like macrophage polarization by stabilizing TAK1. In Experimental cell research, 446, 114469. doi:10.1016/j.yexcr.2025.114469. https://pubmed.ncbi.nlm.nih.gov/39971179/