Glucagon-Like Peptide-1 Receptor Agonists Reduce Liver Stiffness in a Pediatric Metabolic Dysfunction-Associated Liver Disease Cohort and Normalize Disease-Associated Core Gene Expression in an Experimental Model.

Metabolically-dysfunction-associated steatotic liver disease (MASLD) is one of the most common chronic liver diseases in children and is strongly associated with obesity and insulin resistance. In this study, we evaluated the clinical effects of glucagon-like peptide-1 (GLP-1) receptor agonist (RA) therapy in a small, de-identified cohort of pediatric patients with MASLD and investigated potential molecular mechanisms using publicly available transcriptomic datasets from models of liver disease. Longitudinal FibroScan® (Echosens, Paris, France) measurements from seven pediatric patients treated with GLP-1 RAs demonstrated significant reductions in controlled attenuation parameter scores, transient elastography scores, and aspartate aminotransferase levels, indicating improvements in liver steatosis, liver stiffness, and liver inflammatory profiles, respectively. To explore potential mechanisms underlying these observations, we analyzed transcriptomic datasets from methionine-choline-deficient and high-fat diet (HFD) murine models of liver disease. A pattern-matching algorithm identified a core set of 10 genes consistently upregulated in both models and downregulated with GLP-1 RA treatment in the HFD model. These genes are enriched in extracellular matrix remodeling, inflammatory signaling, and fibrogenic pathways associated with hepatic stellate cell activation. Collectively, these findings engender the hypothesis that GLP-1 RAs may prove therapeutic in pediatric MASLD by attenuating inflammation and fibrosis. Although limited by a small cohort size, this integrated clinical-transcriptomic approach supports further investigation of GLP-1 RAs as a fast-follower therapeutic strategy for pediatric MASLD.