Visceral adipose tissue-derived serine protease inhibitor (vaspin), as a secretory adipokine, was reported to exert a protective role on insulin resistance. Recent studies showed that serum vaspin level was downregulated in patients with coronary artery disease. However, whether vaspin exerted specific effects on myocardial injury remains unknown. In this study, we determined to explore the role of vaspin overexpression in myocardial ischaemia/reperfusion (I/R) injury and the underlying mechanisms. Our results showed that the systemic delivery of adeno-associated virus-vaspin to mice reduced myocardial infarct size and apoptosis, and improved cardiac function after reperfusion, accompanied with upregulated autophagic flux and restored lysosomal function in the ischaemic heart. Blockage of the autophagic flux with choroquine mitigated the protection of vaspin on myocardial I/R injury. Moreover, we testified that administration of exogenous recombinant human vaspin on cultured cardiomyocytes suppressed hypoxia/reoxygenation-induced apoptosis, through the AMPK-mTOR-upregulated autophagic flux. Overall, we verified that vaspin functions as an adipokine which can alleviate I/R injury in the heart by suppressing myocardial apoptosis through AMPK-mTOR-dependent activation of autophagic flux, and then provided a potential breakthrough in the treatment of myocardial I/R injury and other ischaemic diseases. (C) 2018 Published by Elsevier Inc.