Protein phosphatases in metabolic dysfunction-associated steatotic liver disease: emerging mechanisms and therapeutic strategies

Metabolic dysfunction–associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease globally, with its severe form, metabolic dysfunction–associated steatohepatitis (MASH), increasing the risk of fibrosis, cirrhosis, and hepatocellular carcinoma. Despite its prevalence, there are limited FDA-approved therapies for MASLD, underscoring the need for novel treatment strategies. Protein phosphatases play critical roles in MASLD pathogenesis as key regulators of metabolic and inflammatory pathways. This review highlights specific phosphatases that are crucial in insulin signaling, lipid metabolism, inflammation, and fibrosis within the liver. While some phosphatases exacerbate disease progression by promoting liver dysfunction, others exhibit protective effects, suggesting potential as therapeutic targets. Altering phosphatase activity may reduce steatosis, improve insulin sensitivity, and alleviate fibrosis. Continued research is essential for developing selective modulators with minimal off-target effects, with the goal of identifying therapeutic approaches to prevent or reverse MASLD progression.