A unimolecular GLP-1 and FGF21 dual agonist for treatment of metabolic dysfunction-associated steatohepatitis

Abstract We report the design and preclinical evaluation of a unimolecular dual agonist, GLP1-ELP-FGF21 (GEF), which integrates GLP-1 and FGF21 signaling by linking GLP-1 and FGF21 through a thermally responsive elastin-like polypeptide (ELP) linker. GEF was engineered for optimal receptor engagement and extended pharmacokinetics through reversible phase separation into a depot upon subcutaneous injection. GEF retained potent in vitro activity at both GLP-1R and FGFR1/β-Klotho pathways and demonstrated robust metabolic and hepatic benefits in a diet-induced murine model of advanced MASH. Treatment with GEF significantly reduced body weight, liver mass, serum glucose levels, and total cholesterol, while also attenuating hepatic inflammation and fibrosis. Molecular and histological analyses revealed suppressed expression of pro-fibrotic and inflammatory genes, reduced steatosis, and enhanced hepatocyte proliferation. Collectively, these findings establish GEF as a promising single-agent, multi-pathway therapeutic for treating advanced MASH.