Physiological roles and therapeutic implications of USP6

Ubiquitin-specific protease 6 (USP6) is a member of deubiquitinating enzyme family, recognized for its essential roles in physiological and pathological processes. USP6 is initially identified as a hominoid-specific enzyme residing on chromosome 17p13. USP6 is involved in regulating cellular functions, signaling pathways, protein degradation, intracellular trafficking, tumorigenesis and immune responses. USP6 is pivotal in signaling pathways, including NF-κB, JAK-STAT, and Wnt, which are fundamental for maintaining cellular homeostasis and mediating stress responses. Dysregulation of USP6 has been implicated in a spectrum of diseases, including bone tumors, breast and colorectal cancers, cranial fasciitis, and neurological disorders such as memory dysfunction. Furthermore, USP6 is involved in emerging therapeutic strategies highlighting its implications for drug development. A number of potential small molecule inhibitors are known to be responsible for suppression of USP6, such as Momelotinib (CYT387), FT385, USP30 Inh-1, -2 and -3, 2,6-Diaminopyridine-3,5-bis(thiocyanate) (PR-619) and so on. This review explores the emerging role of USP6 as a key regulator of cellular signaling pathways, its involvement in disease progression, its physiological functions, and the inhibitors that effectively suppress USP6 activity in detail. The comprehensive study provides insight to enhance our understanding of biological importance and therapeutic interventions of USP6 in drug development.