The diverse functions of ubiquitin-specific protease 47 and its role in diseases

Ubiquitin-specific protease 47 (USP47) is a pivotal deubiquitinase that critically regulates protein post-translational modifications by reversing ubiquitination. Through its N-terminal catalytic domain, which exhibits conserved cysteine protease activity, USP47 specifically recognizes and hydrolyzes ubiquitin chains on substrate proteins. Dysregulation of USP47 disrupts modification of protein ubiquitination, thereby impacting fundamental cellular processes including cell cycle progression, genome stability, and transcription. In this review, we first outline the biological functions of USP47 in DNA repair, cell adhesion, epithelial-mesenchymal transition, and immune evasion mediated via the deubiquitination of key substrate proteins. We then examine its pathogenic roles in cancer, inflammation and antiviral immunity, cardiovascular diseases, neurological disorders and tissue injury, emphasizing context-dependent mechanisms. Furthermore, we summarize recent advances in the development of USP47 inhibitors and propose promising directions for future therapeutic targeting. Overall, this review highlights the important yet still underexplored roles of USP47 in multiple disease pathways.