Here, we find that enhanced SUMOylation of FXR in activated HSCs of fibrotic livers is a key factor restricting the functional benefits of OCA and other FXR agonists and validate that SUMOylation inhibitors combined with OCA potentiates the efficacy of OCA in treatment of liver fibrosis in CCl4, BDL, and NASH models. The gene discussed is NR1H4; the disease is Hepatic fibrosis.