Ubiquitin-specific proteases in hepatitis: bridging molecular mechanisms and therapeutic potential

Abstract Hepatitis is a significant cause of severe liver diseases, including cirrhosis, liver failure, and hepatocellular carcinoma. Current strategies include antiviral drugs, vaccination, and liver transplantation; however, a potential therapeutic strategy is to modulate the ubiquitin-specific proteases (USPs) to develop innovative therapeutic approaches. USPs are a class of deubiquitinating enzymes that play an important role in modulating protein turnover, cell signaling, and immune responses. Recent studies have provided new insights into hepatitis-related therapies for these USPs, as they influence the major signaling pathways and protein synthesis concerning viral replication and liver inflammation. This review provides a detailed analysis of USPs in hepatitis and its manifestations. USPs, such as USP18 in viral hepatitis, modulate the interferon signaling and hence play a critical role in influencing treatment outcomes. USP18, USP15, and USP37 interact with viral proteins, promoting HB&C replication and immune escape. In autoimmune hepatitis, USP4 regulation reduces fibrosis and inflammation, while USP10 promotes autophagy, mitigating nonalcoholic steatohepatitis-related steatosis and fibrosis. This study clarifies the molecular mechanisms involved in USP-mediated pathways and may inform the development of therapeutic approaches for hepatitis and benefit patient recovery and public health.