Therapeutic Efficacy, Mechanistic Insights and Translatability of Semaglutide in the Liver Biopsy-Confirmed GAN DIO-MASH Mouse Model (Supplemental Material)

ABSTRACTGlucagon-like peptide-1 (GLP-1) receptor agonists have emerged as promising therapeutic candidates for metabolic dysfunction-associated steatohepatitis (MASH). Importantly, semaglutide was recently approved as the first GLP-1 based treatment for people with MASH with moderate-to-severe fibrosis. Translational models that recapitulate human MASH are critical for guiding early-stage drug discovery, enabling rigorous efficacy evaluation and facilitating the progression of drug candidates into clinical development. In this study, we investigated the efficacy of semaglutide across an extensive series of experiments in the liver biopsy-confirmed GAN DIO-MASH mouse model, benchmarking outcomes against those from pivotal clinical trials of semaglutide in MASH. Treatment outcomes in the GAN DIO-MASH mouse closely mirrored clinical findings, with extended duration of semaglutide treatment yielding more pronounced improvements in fibrosis histology, consistent with clinical trial outcomes. Importantly, the GAN DIO-MASH mouse recapitulated many human MASH-associated changes in circulating proteins and semaglutide-responsive biomarkers. Collectively, these results support the therapeutic effects of semaglutide in MASH and underscore the reproducibility and clinical translatability of multiple disease-relevant features of the GAN DIO-MASH mouse model, highlighting its applicability as a robust platform for preclinical drug development.