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Introduction
Cancer remains one of the most challenging diseases to understand and treat owing to its complex biology and the diverse mechanisms that drive its progression. Among the myriad of molecular pathways implicated in cancer, the ubiquitin–proteasome system is crucial in maintaining cellular homeostasis by regulating protein degradation and post-translational modifications [1]. The ubiquitin–proteasome system is intricately associated with a multitude of cellular processes, including protein modification, DNA damage repair, cell cycle regulation, signaling pathways, and immune responses. It is also involved in protein activation and localization, the modulation of protein–protein interactions, and protein degradation [2, 3–4]. Furthermore, it plays a pivotal role in the onset and progression of various human diseases, particularly cancer [5, 6, 7, 8–9].
More than 100 deubiquitinating enzymes (DUBs) have been identified in the human genome, which can be classified under six groups: ubiquitin-specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), ovarian tumor-associated protein (OTAP), protease families (ovarian tumor-related proteases, OTUs), JAMM domain-associated metallopeptidases (JAMMs), Machado-Joseph disease proteases (MJDs), and the latest addition, the monocyte chemotactic protein-induced protein family (MCPIP) [10, 11–12]. USPs account for approximately 60% of all DUBs, making them the largest and most diverse among DUB family members [13]. The USP structure comprises three subdomains: palm, thumb, and fingers. These subdomains are arranged with the critical catalytic center located at the junction of the palm and thumb subdomains. The finger subdomains grasp the ubiquitin molecule and position it at the catalytic center. This unique structural feature allows USPs to efficiently recognize and remove ubiquitin from target proteins, thereby regulating protein stability, localization, and function within the cell [14, 15–16]. USPs play critical roles in cellular processes by regulating ubiquitination and deubiquitination, ensuring homeostasis and precise control of functions such as signal transduction, cell cycle progression, and DNA damage repair. USP dysregulation disrupts this balance, contributing to tumorigenesis through mechanisms that include stabilization of oncogenic factors, repression of tumor suppressors, and modulation of the immune microenvironment [17].
The fundamental characteristic of USP39
Ubiquitin-specific protease 39 (USP39), a member of the USP family, was originally discovered during a study on the spliceosome U4/U6-U5 triple-small nuclear ribonucleoprotein complex in yeast [18]. The gene encoding the USP39 protein is located in the 2p11.2 region of human chromosome 2 and is highly conserved...