Unimolecular GLP-1/FGF21 dual agonist reverses advanced MASH in mice, cutting inflammation and fibrosis

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease marked by inflammation and fibrosis, for which effective pharmacological treatments remain limited. Hormones like glucagon-like peptide-1 (GLP-1) and fibroblast growth factor-21 (FGF21) have shown therapeutic promise through complementary metabolic and hepatoprotective actions. GLP-1 agonists primarily target glucose homeostasis and weight, while FGF21 improves lipid metabolism and insulin sensitivity. This study addresses the critical gap for a single therapy that synergistically engages both pathways to tackle multiple drivers of MASH progression.

Researchers designed a unimolecular dual agonist by linking GLP-1 and FGF21 using a thermally responsive elastin-like polypeptide linker to enable sustained drug exposure after subcutaneous administration. Receptor activity was confirmed in cell-based assays. Therapeutic efficacy was evaluated in male C57Bl6/J mice with diet-induced advanced steatohepatitis and fibrosis. The study assessed metabolic measurements, gene expression analyses, protein quantification, and histological assessment of liver tissue. No specific dose or treatment duration was detailed in the abstract.

The unimolecular dual agonist demonstrated potent activity at both target receptors, GLP-1R and FGF21R, and formed a reversible subcutaneous depot that prolonged systemic exposure. Treatment significantly improved body weight, liver mass, blood glucose, and cholesterol levels in mice with advanced liver disease. > The dual agonist notably reduced liver inflammation and fibrosis, accompanied by decreased expression of inflammatory and fibrotic markers, reduced fat accumulation, and increased hepatocyte proliferation. These findings indicate a comprehensive improvement in both metabolic and hepatic features of advanced steatohepatitis.