A unimolecular GLP-1 and FGF21 dual agonist for treatment of metabolic dysfunction-associated steatohepatitis.
This preclinical study designed and tested a novel unimolecular dual agonist that combines glucagon-like peptide-1 (GLP-1) and fibroblast growth factor-21 (FGF21) into a single molecule, connected by a thermally responsive elastin-like polypeptide linker intended to form a sustained-release subcutaneous depot. Receptor activity was first confirmed in cell-based assays. The molecule was then tested in male C57Bl/6J mice fed a diet designed to induce advanced metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis. The study found that treated mice showed improvements in body weight, liver mass, blood glucose, and cholesterol compared to controls. Histological and molecular analyses indicated reductions in liver fat accumulation, inflammation, and fibrosis, along with decreased expression of inflammatory and fibrotic marker genes and increased hepatocyte proliferation. Limitations include the exclusive use of a single male mouse strain, the absence of female animals, and the inherent translational gap between diet-induced rodent models and human MASH. No human data were generated. The authors conclude that this dual-agonist approach warrants further development as a potential chronic liver disease therapy.
Why this grade: All efficacy data were generated exclusively in a diet-induced mouse model (male C57Bl/6J); no human or clinical trial data were included.
Background 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. Methods 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. Results 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. Conclusions 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.
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