Several lines of evidence support our conclusions, which are listed as follows: (1) The expression of KDM3A and NF-κB/P65 were significantly up-regulated in diabetes model and intensive GC model both in vitro and in vivo; (2) Persistent epigenetic signatures, namely histone hypomethylation, were observed even after intensive GC; (3) The KDM3A deletion down-regulated NF-κB/P65 expression, ameliorated hyperglycemia-induced myocardial injury, alleviated oxidative stress, inflammation, and apoptosis in both diabetes and intensive GC models. This evidence concerns the gene KDM3A and diabetes mellitus.