In this study, using the P. acnes plus LPS-induced FHF model, we uncovered that deficiency in EZH2 or inhibition of EZH2 histone methyltransferase activity significantly ameliorated liver injury and improved the survival rates of mice subjected to P. acnes plus LPS-induced FHF, which could be attributed to decreased infiltration and activation of CD4+ T cells in the liver, inhibition of T helper 1 cells and induction of regulatory T cells. Here, EZH2 is linked to TNF receptor 1-associated periodic fever syndrome.