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

Metabolic dysfunction-associated steatohepatitis is a progressive liver disease characterized by inflammation and fibrosis, for which effective pharmacological treatments remain limited. Hormones that regulate metabolism, such as glucagon-like peptide-1 and fibroblast growth factor-21, have shown therapeutic promise through complementary metabolic and hepatoprotective actions. This study aims to develop and evaluate a single molecular therapy that engages both pathways to address multiple drivers of disease progression.

We designed a unimolecular dual agonist by linking glucagon-like peptide-1 and fibroblast growth factor-21 using a thermally responsive elastin-like polypeptide linker to enable sustained drug exposure after subcutaneous administration. Receptor activity was assessed in cell-based assays. Therapeutic efficacy was evaluated in male C57Bl6/J mice with diet-induced advanced steatohepatitis and fibrosis using metabolic measurements, gene expression analyses, protein quantification, and histological assessment of liver tissue.

Here we show that the dual agonist retains potent activity at both target receptors and forms a reversible subcutaneous depot that prolongs systemic exposure. Treatment improves body weight, liver mass, blood glucose, and cholesterol levels in mice with advanced liver disease. We further observe reduced liver inflammation and fibrosis, accompanied by decreased expression of inflammatory and fibrotic markers, reduced fat accumulation, and increased hepatocyte proliferation.

These findings demonstrate that a single long-acting molecule engaging both metabolic hormone pathways improves metabolic and hepatic features of advanced steatohepatitis in a preclinical model. This work supports continued development of unimolecular multi-pathway therapies as a potential strategy for chronic liver disease.