MASLD in children: integrating epidemiological trends with mechanistic and translational advances.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common pediatric liver disease, affecting approximately 10% of children. Its prevalence is rising at an alarming rate, with cases increasingly identified even in early childhood. While MASLD shares key features across the lifespan, its earlier onset reflects developmental vulnerabilities and unique mechanistic drivers. Perinatal influences, including maternal obesity, gestational diabetes, and early-life nutritional exposures, play a central role by disrupting metabolic programming, driving mitochondrial dysfunction, and inducing epigenetic modifications. These early stressors interact with genetic predispositions, such as PNPLA3 and TM6SF2 variants, to amplify susceptibility and shape disease severity. Pediatric MASLD also exhibits distinct histological features, particularly predominant periportal (zone 1) steatosis, inflammation, and fibrosis, which contrast with the centrilobular or pericentral (zone 3) patterns often seen in adults. These findings provide insight into spatial heterogeneity, developmental pathophysiology, and unique disease progression trajectories in children. Addressing MASLD in children requires pediatric-specific approaches to diagnosis, risk stratification, and intervention. By integrating epidemiological trends, mechanistic insights, and translational advances, this Review highlights opportunities for targeted therapies and prevention strategies aimed at mitigating early-life drivers of MASLD, reducing disease burden, and improving long-term outcomes.