The role of deubiquitinating enzymes and their inhibitors in esophageal carcinoma (Review)
Esophageal squamous cell carcinoma (ESCC) is a significantly fatal gastrointestinal malignancy worldwide, with complex proteomic remodeling during its onset and progression. Despite advancements in existing multimodal therapy regimens, the prognosis for advanced patients remains inadequate, necessitating the urgent identification of novel therapeutic targets. The Ubiquitin-proteasome system is the principal regulatory mechanism for intracellular protein homeostasis, with deubiquitinating enzymes (DUBs) serving as crucial 'editors' that reverse ubiquitination modifications, significantly influencing the stability, localization and functional regulation of oncoproteins. This review aims to systematically delineate the complex regulatory network of DUBs in ESCC, comprehensively investigate their specific mechanisms within critical oncogenic signaling pathways, including TGF-β, Wnt/β-catenin, NF-κB and Hippo, as well as their roles in epithelial-mesenchymal transition, epigenetic remodeling and the regulation of the immune microenvironment. Furthermore, this review provides a novel cross-cancer perspective by comparing the similarities and differences of DUBs in ESCC and uterine corpus endometrial carcinoma to determine the conserved and tissue-specific functions of ubiquitin-specific protease (USP)14, USP7 and BRCA1-associated protein 1. Furthermore, the preclinical research progress of small molecule inhibitors and proteolysis-targeting chimeras targeting DUBs was also assessed to identify the theoretical basis and translational pathway for the development of next-generation precision oncology therapies.