Abstract Body: Heart failures with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF) have been recognized as the leading cause of morbidity and mortality worldwide. Histone lysine demethylase KDM5B, an important anti-tumor drug target, has been involved in several cardiovascular diseases. However, its role in heart failure remains largely unknown. In the current study, we found that the expression of KDM5B were significantly enhanced and KDM5B’s downstream substrate: the methylation level of H3K4me3 was decreased in the mouse hearts of both trans-aortic constriction (TAC)-induced HFrEF and high fat diet (HFD) with Nω-nitro-L-arginine methyl ester (L-NAME) (two-hit)-induced HFpEF. By generating a tamoxifen-induced cardiomyocyte- (CM-KO) and a myofibroblast- (MF-KO) specific KDM5B Cre-loxP conditional knockout mice, specifically, we further found that either KDM5B CM-KO or MF-KO mouse significantly ameliorated pathological ventricular remodeling, fibrosis and rescued the cardiac dysfunction phenotypes induced by TAC or the two-hit models, specifically. Furthermore, pretreatment of a KDM5B specific inhibitor TK-129, which was previously identified by our group, also significantly attenuated myocardial hypertrophy, fibrosis and improved cardiac dysfunction in the two mouse heart failure models. Our findings demonstrated, for the first time, that genetic deficiency of KDM5B in either cardiomyocytes or myofibroblasts in vivo or pharmacological inhibition of KDM5B display a similar therapeutic effect in the pathological cardiac remodeling and heart failure in both pressure overload-induced HFrEF and HFpEF mouse models, suggesting that KDM5B is a potential therapeutic target for these two different HFs.