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Type 2 diabetes, a global health concern has been considered as major risk factor for cardiovascular diseases. Hinokinin, an emerging bioactive lignin, is reported to show wide range of pharmacological activities. However, the protective role and mechanisms of Hinokinin against type 2 diabetes-mediated cardiotoxicity are still remains unknown. An experimental type 2 diabetic mice model was created by treating animals with high fat diet for four weeks and intraperitoneal injection of streptozotocin (35 mg/kg body weight). Post-type 2 diabetic induction, animals orally treated with Hinokinin (20 or 40 mg/kg body weight) for six weeks. The type 2 diabetic mice exhibited a rise in blood glucose level as well as glycated hemoglobin (HbA1c %), decrease in weekly body weights, decrease in food intake, reduction in absolute heart weight, fall in serum insulin level with altered lipid profile and cardiac functional damage. Diabetic mice treated with Hinokinin attenuated hyperglycemia, dyslipidemia and cardiac dysfunction. In addition, Hinokinin ameliorated histological alterations, fibrosis and glycated proteins in HFD/STZ-induced mice. Type 2 diabetic condition in mice exacerbated oxidative stress, inflammatory status and apoptosis. Hinokinin treatment significantly assuaged oxidative stress, inflammation and apoptosis and elevated antioxidant defenses in diabetic heart. The underlying mechanisms for such mitigation involved the modulation of Nrf2/Keap1/ARE pathway, MAPKs (JNK, p38 and ERK 1/2) and TLR4/MyD88/NF-κB mediated inflammatory pathways and mitochondrial-dependent (intrinsic) apoptosis pathway. In conclusion, the results of this study provided clear evidence that Hinokinin protects against HFD/STZ (type 2 diabetes)-induced cardiac injury by alleviating oxidative stress, inflammation and apoptosis., (Copyright © 2021. Published by Elsevier Masson SAS.)