Diabetes mellitus (DM) is a risk factor for abnormal heart development, but the molecular mechanism remains obscure. Histone deacetylase 11 (HDAC11), the most recently identified histone deacetylase, is the sole member of class IV HDACs. However, its role in diabetic cardiac injury is still poorly understood. In the present study, we attempted to explore the effects of HDAC11 on fructose (Fru)-induced cardiac injury using the wild type (HDAC11(+/+)) and knockout (HDAC11(-/-)) mice. The results indicated that HDAC11 was significantly expressed in human and mouse diabetic heart failure (DHF) hearts. HDAC11(-/-) reduced the body weight, inguinal fat-pad mass, and elevated blood pressure in Fru-fed mice. Compared to HDAC11(+/+)/Fru group, cardiac function was significantly improved in HDAC11(-/-)/Fru mice. HDAC11(-/-)/Fru mice exhibited reduced cardiac triacylglycerol (TG), total cholesterol (TC) and free fatty acid (FFA) levels, along with decreased mRNA levels of lipid synthesis-, lipid storage- and lipid oxidation-associated genes. In addition, HDAC11 attenuated apoptosis, oxidative stress and inflammation in the heart of Fru-fed mice, as evidenced by the reduced cleavage of Caspase-3, nicotinamide adenine dinucleotide phosphate (NADPH), and xanthine oxidase (XOD) activity, enhanced superoxide dismutase (SOD) activity, as well as the decreased interleukin 1 beta (IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) levels, which was accompanied with down-regulated p-NF-kappa B. The results above were verified in Fru-treated primary cardiomyocytes isolated from HDAC11(+/+) or HDAC11(-/-) mice. Intriguingly, suppressing the expressions of anti-oxidants using zinc protoporphyrin (ZnPP) or siNrf-2 siRNA markedly abolished the results that HDAC11 suppression -induced reduction of apoptosis, reactive oxygen species (ROS) production, inflammation, as well as the improvement of dyslipidemia in Fru-incubated primary cardiomyocytes. Thus, ROS production was responsible for HDAC11-modulated diabetic heart injury. These findings suggested that suppressing HDAC11 has therapeutic potential for treating diabetes mellitus-associated cardiac injury. (C) 2018 Published by Elsevier Inc.