Deubiquitinating enzymes in cervical cancer: Molecular mechanisms and therapeutic implications (Review).

Cervical cancer (CC) ranks among the most prevalent gynecological malignancies, constituting a persistent and substantial global health challenge ( 1 ). While advances in human papillomavirus (HPV) screening and vaccination have improved prevention and early detection, a notable number of patients still experience delayed diagnosis, treatment resistance, recurrence and poor clinical outcomes. Thus, elucidating the molecular mechanisms that underlie CC initiation and progression is fundamental to improving disease management and refining therapeutic strategies ( 2 ). Ubiquitination and deubiquitination are essential processes for maintaining cellular function and homeostasis ( 3 ). Ubiquitination is regulated by a coordinated enzymatic cascade involving ubiquitin-activating enzyme E1, ubiquitin-conjugating enzyme E2 and ubiquitin ligase E3 ( 3 ). This process is reversed by deubiquitination, which is mediated by deubiquitinating enzymes (DUBs) ( 3 ). Notably, >100 DUBs have thus far been identified and classified into nine superfamilies based on sequence and structural features ( Fig. 1 ): Ubiquitin-specific peptidase (USP), ovarian tumor-related protease (OTU), ubiquitin C-terminal hydrolase (UCH), Machado-Joseph domain-containing protease (MJD), JAMM/MPN domain-associated (JAMM/MPN) metallopeptidase, motif-interacting with ubiquitin-containing novel DUB (MINDY), monocyte chemotactic protein-induced protein (MCPIP), permuted papain fold peptidases of dsRNA viruses and eukaryotes (PPPDE) and zinc finger-containing ubiquitin peptidase 1 (ZUP1) families ( 3 ). A subgroup termed pseudo-DUBs has been proposed to describe DUB family members that lack canonical catalytic activity because of defects in key residues or domains ( 4 ). However, subsequent studies have suggested that this classification is not absolute. Several proteins previously categorized as pseudo-DUBs, including USP39 ( 5 ), USP53 ( 6 ), USP54 ( 6 ), PSMD7 ( 7 ), eukaryotic translation initiation factor 3 subunit F (EIF3F) ( 8 ) and STAMBPL1 ( 9 ), retain or exhibit deubiquitinating activity under specific conditions. Enzymatic activity has also been confirmed for PPPDE1 ( 10 ), MCPIP1 ( 11 ) and MCPIP4 ( 12 ). These findings indicate that the classification of pseudo-DUBs is dynamic and should be interpreted cautiously as functional evidence continues to emerge. DUBs function by recognizing ubiquitin-tagged proteins and hydrolyzing isopeptide bonds between ubiquitin molecules, or between ubiquitin and substrate proteins. Through these actions, DUBs regulate cell cycle progression, DNA damage repair, apoptosis, immune regulation and signal transduction, among other cellular events ( 13 , 14 ). Growing evidence has shown that dysregulated DUB activity contributes to the development and progression of various malignancies, including gynecologic cancer ( 15 - 17 ). Although several studies have examined DUBs in CC ( 13 , 15 , 18 ), a comprehensive review of their molecular functions, regulatory mechanisms and therapeutic relevance is lacking. The present review systematically summarizes current research on DUBs in CC, with emphasis on their roles in HPV-associated carcinogenesis, signaling pathway regulation, tumor progression, therapy response and potential DUB-targeted therapies.

In conclusion, current evidence indicates that DUBs are biologically important and potentially actionable regulators in CC, although the depth and maturity of available evidence vary substantially among individual family members. Therefore, future research should focus less on simply expanding the list of CC-associated DUBs, and more on prioritizing those with the strongest clinical and translational potential. Among the DUBs reviewed, USP7 appears to be the most promising near-term candidate because it is supported by relatively consistent evidence linking dysregulated expression, clinicopathological relevance, functional importance and therapeutic tractability. USP8 has also emerged as a strong candidate based on its prognostic associations and in vivo functional validation. In addition, USP21, USP53 and OTUD5 warrant particular attention in the context of radiotherapy, where DUB-based patient stratification and radiosensitization strategies may offer practical clinical benefits. From a therapeutic perspective, small molecule inhibition of oncogenic DUBs currently represents the most feasible route for clinical translation in CC. By contrast, DUBTAC-based approaches remain highly promising but are still at an early developmental stage and will require substantial optimization before clinical application in CC becomes realistic. Subsequent research should prioritize three key directions: i) Validation of leading DUB candidates in clinically annotated patient cohorts; ii) evaluation in treatment-oriented preclinical models; and iii) biomarker-guided development of DUB-targeted strategies. Ultimately, the greatest near-term progress is likely to come from concentrated work on a limited number of well-supported DUBs rather than from broad but superficial expansion of candidate lists.