Ketogenesis as a Metabolic Checkpoint in MASLD: Implications for Disease Progression and Therapy

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, encompassing a spectrum from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis and hepatocellular carcinoma. Increasing evidence indicates that disease progression is driven not by hepatic triglyceride accumulation alone but by the metabolic partitioning of excess fatty acids between adaptive and maladaptive pathways. Ketogenesis, traditionally viewed as a fasting-induced mechanism for disposing of excess acetyl-CoA, is now recognized as a key regulator of hepatic metabolic homeostasis, coordinating mitochondrial substrate utilization, carbon flux and systemic metabolic adaptation. In addition to serving as oxidative fuels, ketone bodies, particularly β-hydroxybutyrate, function as signalling metabolites that modulate inflammation, oxidative stress, mitochondrial function and epigenetic regulation. Despite increased fatty acid delivery in obesity and insulin resistance, ketogenic capacity becomes progressively impaired during MASLD, promoting mitochondrial acetyl-CoA accumulation, oxidative stress and diversion of carbon toward lipotoxic lipid synthesis while reducing protective β-hydroxybutyrate signalling. This review examines ketogenesis as an integrative metabolic checkpoint linking fatty acid oxidation, lipid metabolism, mitochondrial function and immune signalling in MASLD. We discuss how impaired ketogenic flux contributes to hepatocellular injury, fibrosis and metabolic inflexibility, and evaluate the therapeutic potential of restoring ketogenesis to prevent disease progression.