In summary, through pharmacological and genetic manipulations in HSCs and mouse liver fibrosis models and transcriptomic profiling of HSCs, we demonstrate that H3K27 methyltransferase EZH2 and demethylase JMJD3 regulate Bambi, Cdkn1a, Gadd45a and Gadd45b genes in HSCs, which is functionally associated with the antagonistic roles of EZH2 and JMJD3 in HSCs activation, and with the anti-proliferative, pro-apoptotic and anti-fibrotic benefits of EZH2 inhibitor DZNep treatment in both HSCs and mice. Here, MBD2 is linked to Hepatic fibrosis.