UCHL3, also known as ubiquitin C-terminal hydrolase 3, is a cysteine protease that conducts deubiquitination and deneddylation activities. It plays a crucial role in cell cycle regulation, DNA repair, and apoptosis, and is involved in maintaining protein homeostasis within cells. Dysregulation of UCHL3 has been associated with neurodegenerative diseases, and it has emerged as a promising therapeutic target for certain cancers due to its ability to stabilize oncoproteins [2].

UCHL3 depletion significantly decreased anaplastic thyroid cancer (ATC) progression, stem-like and metastasis, and increased cell sensitivity to chemotherapy. It was found that UCHL3 stabilizes YAP in ATC in a deubiquitylation activity-dependent manner, and TEAD4 activates UCHL3 transcription by binding to its promoter [1]. In hepatocellular carcinoma (HCC), UCHL3 binds to and stabilizes EEF1A1 through deubiquitination, promoting HCC cell migration, stemness, and drug resistance [3]. In glioma stem cells, targeted depletion of the UCHL3-POLD4 axis reduced self-renewal, tumorigenic capacity, and radiation resistance [4]. In bladder cancer, depletion of UCHL3 in cancer cells delayed tumorigenesis in vitro and in vivo, while its overexpression boosted cell proliferation, invasion, and migration [5]. In cervical cancer, knockdown of UCHL3 inhibited cell growth, migration, and invasion in vitro and cancer development and metastasis in vivo [6].

In conclusion, UCHL3 is essential for multiple cellular processes, especially in maintaining protein stability through deubiquitination. The use of UCHL3 knockout or conditional knockout mouse models has revealed its significant role in promoting the progression of various cancers, including ATC, HCC, glioblastoma, bladder cancer, and cervical cancer. These findings suggest that UCHL3 could be a potential therapeutic target for treating these malignancies.