<p>Fatty liver disease, hepatitis, hepatocellular carcinoma (HCC), and other major liver diseases are significant global public health challenges. A deeper understanding of the underlying mechanisms driving the onset and progression of these diseases, along with the exploration of potential targeted therapies, is of critical importance. The ubiquitin-proteasome system (UPS) plays a crucial role in protein degradation in eukaryotic cells. Deubiquitinases (DUBs) are key enzymes that regulate the balance between ubiquitination and deubiquitination, and they are involved in a wide range of cellular physiological processes. Dysregulation of DUBs is frequently observed in various liver diseases, including chronic liver diseases (CLDs) and HCC. Targeted therapies, with their high selectivity and low side effects, have attracted significant attention. Small molecules targeting DUBs have shown promising therapeutic effects in the treatment of major liver diseases. Given the important role of DUBs in liver diseases, this review focuses on summarizing the potential mechanisms through which DUBs contribute to the development of metabolic dysfunction-associated steatotic liver disease (MASLD), viral hepatitis, liver fibrosis, and HCC, as well as the application of DUB inhibitors. It aims to provide a theoretical foundation for basic research on major liver diseases and propose strategies for their treatment.</p>