Structure and function of the highly homologous deubiquitinases ubiquitin specific peptidase 25 and 28: Insights into their pathophysiological and therapeutic roles

Deubiquitination is the reverse process of ubiquitination, an important protein post-translational modification. Deubiquitination is assisted by deubiquitinating enzymes (DUBs), which catalyze the hydrolysis and removal of ubiquitin chains from targeted proteins and play an important role in regulating protein stability, cell signaling transduction, and programmed cell death. Ubiquitin-specific peptidases 25 and 28 (USP25 and USP28), important members of the USP subfamily of DUBs, are highly homologous, strictly regulated, and closely associated with various diseases, such as cancer and neurodegenerative diseases. Recently, the development of inhibitors targeting USP25 and USP28 for disease treatment has garnered extreme attention. Several non-selective and selective inhibitors have shown potential inhibitory effects. However, the specificity, potency, and action mechanism of these inhibitors remain to be further improved and clarified. Herein, we summarize the structure, regulation, emerging physiological roles, and target inhibition of USP25 and USP28 to provide a basis for the development of highly potent and specific inhibitors for the treatment of diseases, such as colorectal cancer, breast cancer and so on.