Ketone metabolites in metabolic dysfunction-associated steatotic liver disease progression: optimizing keto-therapeutic strategies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) ranges from simple steatosis to hepatocellular injury, inflammation, and fibrosis, ultimately leading to end-stage liver disease. Despite its rising prevalence, treatment options remain limited, highlighting the need for novel therapeutic strategies. In recent years, ketone metabolism has emerged as a key modulator of hepatic metabolic health. Hepatic ketogenesis provides a mechanism for fatty acid mobilization. Endogenously synthesized ketone metabolites can then provide energy for hepatic nonparenchymal cells and extrahepatic tissues. Ketones also function as signaling molecules that can reduce key pathological drivers of MASLD progression. Impaired ketogenesis is observed in MASLD, contributing to metabolic inflexibility and liver dysfunction. Conversely, ketogenic interventions, including exogenous ketone supplementation and ketogenic diets, have been shown to be hepatoprotective, attenuating steatosis, inflammation, and fibrosis. Ketogenic enzyme loss- and gain-of-function studies have highlighted the roles of ketogenesis, ketolysis, and ketone metabolite conversion in MASLD, providing insights to refine keto-therapeutic strategies for disease management. This review seeks to offer a thorough examination of ketone metabolism in MASLD, exploring the mechanistic roles of ketone metabolites in disease progression, and highlighting gaps in the current literature to optimize keto-therapeutics and combat MASLD progression.