Deubiquitinases in liver diseases: from mechanisms to targeted therapy

Area of Science:

• Biochemistry
• Molecular Biology
• Hepatology

Background:

• Major liver diseases, including fatty liver, hepatitis, and hepatocellular carcinoma (HCC), pose significant global health challenges.
• The ubiquitin-proteasome system (UPS) regulates protein degradation, with deubiquitinases (DUBs) controlling ubiquitination/deubiquitination balance.
• DUB dysregulation is implicated in chronic liver diseases (CLDs) and HCC, highlighting their pathogenic role.

Purpose of the Study:

• To review the mechanisms by which DUBs contribute to liver diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD), viral hepatitis, liver fibrosis, and HCC.
• To summarize the therapeutic potential of DUB inhibitors in treating major liver diseases.
• To provide a foundation for research and treatment strategies for liver diseases.

Main Methods:

• Literature review focusing on the role of DUBs in liver disease pathogenesis.
• Analysis of studies investigating DUBs in MASLD, viral hepatitis, fibrosis, and HCC.
• Examination of preclinical and clinical data on DUB inhibitors as therapeutic agents.

Main Results:

• DUBs play multifaceted roles in the development and progression of various liver pathologies.
• Targeted inhibition of specific DUBs demonstrates significant therapeutic efficacy in preclinical models of liver disease.
• Small molecule DUB inhibitors offer a promising avenue for selective and low-side-effect treatments.

Conclusions:

• DUBs are critical regulators in liver disease development, making them attractive therapeutic targets.
• DUB inhibitors represent a promising strategy for novel treatments of MASLD, viral hepatitis, fibrosis, and HCC.
• Further research into DUBs will advance our understanding and treatment of major liver diseases.