Our results indicate the vismodegib treatment in a dietary nutrient excess model of murine NASH has several salutary effects including: (i) a decrease in hepatocyte injury despite lipid loading of the hepatocytes; (ii) inhibition of DR5 upregulation and DR5-mediated liver injury; (iii) a reduction in hepatic markers of macrophage accumulation and activation; and (iv) decreased fibrosis. Here, TNFRSF10B is linked to metabolic dysfunction-associated steatohepatitis.