Introduction & Objective: Metabolic dysfunction-associated steatohepatitis (MASH) ncreases the risk for the development of hepatocellular carcinoma (HCC). The present study aimed to evaluate the efficacy of semaglutide, a glucagon-like-receptor (GLP1R) agonist, on disease progression in the translational GAN diet-induced obese (DIO) and biopsy-confirmed mouse model of MASH with advanced fibrosis and HCC.
Methods: Male C57BL/6J mice were fed the GAN diet high in fat, fructose, and cholesterol for 54 weeks (DIO-MASH-HCC mice) prior to treatment intervention. Only mice with liver biopsy-confirmed NASH and advanced fibrosis were included and stratified into study groups. DIO-MASH-HCC mice (n=15-16 per group) received vehicle or semaglutide (30 nmol/kg) once daily for 14 weeks. Untreated DIO-NASH-HCC mice (n=10) were terminated at baseline. Endpoints included within-subject change in nonalcoholic fatty liver disease activity score (NAS), fibrosis stage, quantitative histology, tumor classification and macroscopic tumor count/diameter.
Results: DIO-MASH-HCC mice demonstrated progressive liver tumor burden over the 14-week study period. Tumors showed consistent architectural, cytologic and molecular features of poor prognostic HCC. Semaglutide promoted ≥2-point improvement in NAS, supported by beneficial changes in quantitative histological markers of steatosis and inflammation. While not improving fibrosis, semaglutide substantial reduced tumor numbers, tumor size and histological markers of proliferation (Ki67) and progenitor cell activation (CK19).
Conclusion: Consistent with a recent clinical trial, semaglutide improves MASH while not promoting fibrosis regression in GAN DIO-MASH-HCC mice. Notably, semaglutide markedly lowers HCC burden in the model. Collectively, our data highlights the suitability of GAN DIO-MASH-HCC mice for profiling novel drug therapies targeting MASH-driven HCC.
M. Feigh: Employee; Gubra. M. Tozzi: None. H.H. Hansen: Employee; Gubra.
