Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) impacts nearly a quarter of the world's population and encompasses a range of disease states, from simple steatosis to more advanced stages like metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, and cirrhosis. A key driver of disease progression is mitochondrial dysfunction, characterized by impaired fatty acid oxidation and an overall decline in mitochondrial health. Emerging evidence has implicated ceramides-bioactive sphingolipids that serve roles in apoptotic pathways and as signals of nutrient excess-as important contributors to this dysfunction. Ceramide accumulation within mitochondria mirrors impairments seen in MASLD, specifically elevations in oxidative stress, disrupted fatty acid oxidation, and impaired mitochondrial dynamics. Ceramides may serve as an important molecular link between nutrient overload and mitochondrial dysfunction in the pathogenesis of MASLD. Given the limited availability of effective pharmacologic therapies for MASLD, lifestyle interventions like dietary modification and physical activity remain the cornerstone of disease management worldwide. In this review, we provide an overview of the current understanding of the role of ceramides in mediating the effects of diet and exercise on MASLD through their influence on mitochondrial health.