Ubiquitin-specific proteases in ovarian cancer: molecular mechanisms and therapeutic implications

Ovarian cancer (OC) remains one of the most lethal gynecological malignancies, largely due to late-stage diagnosis, frequent recurrence, and the development of resistance to standard therapies. These clinical challenges highlight the urgent need for a deeper understanding of the biological processes driving OC and the identification of novel therapeutic targets. The ubiquitin-proteasome system is a central mechanism for selective protein degradation. Accumulating evidence indicates that deubiquitinases, particularly ubiquitin-specific proteases (USPs), are key regulators of oncogenic signaling and therapy response in OC. This review provides a comprehensive overview of how dysregulated USPs shape major cancer hallmarks in OC, including cell-cycle control, DNA damage repair and genomic stability, apoptosis, metastasis, metabolic reprogramming, and immune evasion. We further summarize advances in developing USP-directed pharmacologic inhibitors, discuss emerging translational strategies, and evaluate the rationale for combining USP inhibition with established treatments such as platinum-based chemotherapy and poly-ADP ribose polymerase inhibitors (PARPis) to overcome resistance. Collectively, understanding USP-dependent networks may facilitate the identification of novel biomarkers and therapeutic targets, offering new strategies for precision treatment in OC.