Deubiquitinase-Driven Oncogenic Signalling in Gastric Cancer: Mechanistic and Therapeutic Insights into USP7 and USP22

Abstract

Gastric Cancer (GC) remains one of the leading causes of cancer- related mortality worldwide, largely because of late diagnosis, tumour heterogeneity, and metastatic progression. Increasing evidence highlights the critical role of the Ubiquitin– Proteasome System (UPS) in cancer biology. Among its components, Deubiquitinating Enzymes (DUBs) have emerged as key regulators of oncogenic signalling pathways. In particular, Ubiquitin-Specific Proteases 7 (USP7) and 22 (USP22) have attracted considerable attention because of their roles in tumour progression, metastasis, and therapeutic resistance in GC. A comprehensive literature-based review was conducted using major scientific databases, including PubMed, Scopus, Google Scholar, and Web of Science. Relevant studies investigating the molecular mechanisms, signalling pathways, and clinical implications of USP7 and USP22 in GC were systematically reviewed and analysed to provide a comprehensive synthesis of the current evidence. The available evidence demonstrates that USP7 and USP22 regulate multiple oncogenic signalling pathways involved in cell proliferation, apoptosis, epithelial– mesenchymal transition, and metastasis. These deubiquitinases modulate the stability and activity of key regulatory proteins, including p53, MYC, and other transcriptional regulators. Dysregulation of USP7 and USP22 is associated with tumour aggressiveness, poor prognosis, and increased metastatic potential in GC. Targeting deubiquitinase-mediated signalling represents a promising therapeutic strategy for GC. Inhibitors of USP7 and USP22 have shown encouraging antitumour activity in preclinical studies by disrupting oncogenic signalling pathways and restoring tumour-suppressive functions. A better understanding of the molecular mechanisms regulated by these enzymes may facilitate the development of more effective targeted therapeutic strategies. USP7 and USP22 play pivotal roles in GC progression by regulating multiple oncogenic signalling networks. Further investigation into their molecular functions and therapeutic potential may provide new opportunities for improving the diagnosis, prognosis, and treatment of GC.