Deubiquitinases in metabolic diseases, fibrosis and cancer of the liver.

Obesity is a key driver of the progression from metabolic dysfunction-associated steatotic liver disease (MASLD), to metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis, and hepatocellular carcinoma (HCC). Excess adiposity and elevated circulating fatty acids disrupt metabolic, inflammatory, and signaling pathways, creating conditions permissive for hepatic injury, inflammation, fibrogenesis, and carcinogenesis. One of the mechanisms that regulates these pathways is ubiquitylation, a post-translational modification that controls protein degradation and cellular signaling. Deubiquitinases (DUBs) counterbalance this process by removing ubiquitin chains, thereby maintaining cellular homeostasis. This review examines the role of DUBs in obesity-induced MASLD progression, focusing on how dysregulated DUB expression affects insulin signaling, lipogenesis, inflammation, and oxidative stress. While DUBs have been extensively studied in cancer and metabolic syndrome, their therapeutic potential in obesity-related MASH, liver fibrosis, and HCC has not been fully explored. By synthesizing clinical and experimental evidence, we highlight DUBs as promising precision medicine tools for both patient stratification and therapeutic intervention. This review emphasizes the critical need for further translational research to develop DUB-targeted strategies for early intervention in MASLD progression.