β-Lapachone, an NQO1 activator, alleviates diabetic cardiomyopathy by regulating antioxidant ability and mitochondrial function

•Finding new therapeutic drugs for diabetic cardiomyopathy (DC), the major mortality of diabetes mellitus (DM), is urgent and necessary. Oxidative stress, the increasing of ROS, is the leading cause of DC.•Lap, a plant-extracted compound, can maintain heart functions and protect cardiomyocytes from DM-induced damages through reducing oxidative stress, increasing the antioxidant regulator and enzymes, decreasing inflammation, maintaining mitochondrial activity and biogenesis, decreasing heart size, and maintaining heart function.•With the detailed investigations in vitro, the protective effects of Lap are through the interaction of NQO1, Sirt 1, and mitochondrial activity.•To the best of our knowledge, the regulation of Lap on increasing mitochondria activity and biogenesis is a novel discovery in cardiomyocytes.•With the protection effects on cardiomyocytes, Lap has a great potential serving as a therapeutic agency for DC. Diabetic cardiomyopathy (DC) is one of the major lethal complications in patients with diabetes mellitus (DM); however, no specific strategy for preventing or treating DC has been identified. This study aimed to investigate the effects of β-lapachone (Lap), a natural compound that increases antioxidant activity in various tissues, on DC and explore the underlying mechanisms. As an in vivo model, C57BL/6 mice were fed with the high-fat diet (HF) for 10 weeks to induce type 2 DM. Mice were fed Lap with the HF or after 5 weeks of HF treatment to investigate the protective effects of Lap against DC. In the two in vivo models, Lap decreased heart weight, increased heart function, reduced oxidative stress, and elevated mitochondrial content under the HF. In the in vitro model, palmitic acid (PA) was used to mimic the effects of an HF on the differentiated-cardiomyoblast cell line H9c2. The results demonstrated that Lap reduced PA-induced ROS production by increasing the expression of antioxidant regulators and enzymes, inhibiting inflammation, increasing mitochondrial activity, and thus reducing cell damage. Via the use of specific inhibitors and siRNA, the protective effects of Lap were determined to be mediated mainly by NQO1, Sirt1 and mitochondrial activity. Heart damage in DM is usually caused by excessive oxidative stress. This study showed that Lap can protect the heart from DC by upregulating antioxidant ability and mitochondrial activity in cardiomyocytes. Lap has the potential to serve as a novel therapeutic agent for both the preven