Sepsis is defined as organ dysfunction caused by an abnormal host immune response to infection and is the most common cause of in-hospital mortality [1], [2]. Approximately 50 million patients were diagnosed with sepsis worldwide, and approximately 50 % of patients with sepsis developed myocardial dysfunction, as the heart is the most vulnerable organ to sepsis [3], [4]. Sepsis-induced myocardial dysfunction (SIMD) is characterized by dilation of the ventricle, decreased ejection fraction, and reduced contractility [4], [5], and the mortality rates associated with SIMD are significantly increasing [6], [7]. The pathogenesis of SIMD includes the overproduction and release of circulating myocardial inhibitory substances (such as TNF-α and IL-1β), inhibition of adrenergic pathways, overproduction of reactive oxygen species, abnormalities in calcium handling, and mitochondrial dysfunction [8]. However, the physiopathological mechanisms of SIMD are not completely understood.

The phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is an important intracellular signal transduction pathway that regulates biological homeostasis by modulating cell survival, growth, proliferation, angiogenesis, transcription, translation, autophagy, and apoptosis [9], [10], [11], [12], [13]. The PI3K/AKT/mTOR signaling pathway plays an important role in oxygen delivery, glucose utilization, and mitochondrial biogenesis during chronic ischemic heart failure [14]. Moreover, inflammatory factors and apoptosis are reduced upon the activation of the PI3K/AKT/mTOR signaling pathway, and myocardial ischemia reperfusion injury in myocardial cells is alleviated [15].

Neutrophil elastase (NE) is a major serine protease released by neutrophils, which mediates innate host defense against bacterial infection and plays an important role in the killing of pathogens, regulating inflammation, and tissue homeostasis [16], [17]. However, excessive NE release can cause tissue damage in inflammatory diseases, including pneumonia [18], acute lung injury [19], kidney injury [20], rheumatoid arthritis [21], and cardiopulmonary diseases [22]. Sivelestat is a highly specific and effective synthetic inhibitor of neutrophil elastase and is widely used for treating acute lung injury and acute respiratory distress syndrome [23]. Moreover, it can alleviate the organ damage caused by excessive NE release [20], [24], [25]. However, the mechanism underlying the cardioprotective role of sivelestat is not clear. Accordingly, the current study aimed to explore the underlying protective mechanism of sivelestat against SIMD.