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. Fatty liver disease can worsen over time and lead to liver inflammation and scarring, which can seriously affect health. Current treatments are limited, especially for people with advanced disease. This study aimed to develop a new type of medicine that targets more than one disease pathway at the same time. The researchers created a single long-acting drug by combining two natural hormones that help regulate metabolism and protect the liver. This drug was tested in mice with advanced fatty liver disease to see how it affected body weight, blood sugar, cholesterol, and liver health. The treatment improved metabolic health and reduced liver inflammation and scarring. These findings suggest that combining multiple beneficial actions into one medicine could be a promising approach for future treatments of advanced fatty liver disease. Sirohi et.al. develop a unimolecular dual agonist targeting both GLP-1 and FGF21 for the treatment of advanced metabolic liver disease. The dual agonist improves metabolic parameters, reduces liver inflammation and fibrosis, and promotes liver repair in a preclinical murine model.