Here, we have shown that EZH2 deficiency established by gene knockout or inhibition of EZH2 with a small-molecule inhibitor impairs the immune responses of monocyte-derived and liver-resident DCs, which corresponds with the amelioration of bacteria-induced liver injury, increasing the survival rate of mice subjected to P. acnes plus LPS-induced FHF. This evidence concerns the gene EZH2 and TNF receptor 1-associated periodic fever syndrome.