Sepsis is a life-threatening organ dysfunction caused by an abnormal host response to infection. It is a common type of severe infectious disease syndrome, characterized by a high incidence rate and mortality rate [1]. Up to 30 million people worldwide are affected by sepsis annually, resulting in around 600,000 deaths, according to a survey by the World Health Organization [2]. The heart is a commonly affected organ system in sepsis, manifesting as a decline in myocardial contractility and a reduction in ejection fraction [3]. The pathogenesis of sepsis-induced myocardial injury is incredibly complex, making it a focal point and challenge for the medical community. Current research suggests that the mechanisms underlying this condition involve oxidative stress response, mitochondrial dysfunction, and Toll-like receptor activity [4], [5]. In addition to the inflammation and oxidative stress caused by infection, mitochondrial autophagy is also a significant contributor to sepsis-induced myocardial injury [6].

Mitochondria autophagy is the primary mechanism for cellular mitochondrial renewal and normal function status. It is also a crucial compensatory response in cardiac cells under pathological conditions. Currently, PTEN induced putative kinase 1 (PINK1)/Parkin, autophagy-related gene (ATG5), p62/Sequestosome 1 and other proteins are widely believed to mediate the mitochondrial autophagy pathway [7], [8], [9]. Evidence of myocardial mitochondrial structure damage and functional alterations associated with sepsis has been observed in a variety of sepsis animal models [10]. Furthermore, pathological examination of heart tissue in patients who died from sepsis also revealed alterations in myocardial mitochondrial structure [11]. The comprehensive analysis of mitochondrial metabolism in septic cardiomyopathy revealed an association between septic cardiomyopathy and mitochondrial dysfunction [12]. Additionally, Zhou et al. have proven that TMBIM6 can improve mitochondrial quality, thereby reducing sepsis-related myocardial injury [13]. Similarly, Zhu et al. have discovered that enhancing mitochondrial quality significantly prevents endotoxemia-induced myocardial dysfunction [14]. These findings indicated that the mitophagy is closely to sepsis induced myocardial damage. Jiang et al. confirmed that iridoid acid can enhance mitochondrial autophagy in cardiac cells through mitochondrial dysfunction, oxidative stress, and apoptosis [15]. Cao et al. also verified that Pae-jiu injection liquid can induce mitophagy in cardiac mitochondria, thereby providing cardioprotective effects against mouse sepsis-induced cardiac disease models [16]. Hence, it is a crucial pathway to improve the cardiac injury caused by sepsis via promoting mitochondrial autophagy in cardiomyocytes. Identifying the relevant targets for mitochondrial autophagy may serve as a significant approach to treating and researching sepsis-induced cardiomyopathy.

Recent research has shown that the progression of sepsis is closely related to circadian rhythm changes, and these changes can be used as a marker for the severity of the condition [17]. Brain and muscle arnt-like protein-1 (BMAL1) is a key protein in the transcription-translation feedback loop (TTFL) of the circadian rhythm factors. Research has confirmed that the deletion of the BMAL1 gene in liver cells can disrupt the transcription response of the feeding cycle in the liver, leading to elevated sensitivity to lipopolysaccharide (LPS) in liver cells and reduced survival rates in sepsis models [18]. Hence, we speculate that BMAL1 may also be closely associated with the progression of cardiovascular disease in sepsis. Additional research has confirmed that the knockout of the BMAL1 gene can induce mitochondrial autophagy damage and mitochondrial dysfunction, leading to myocardial cell function impairment [19]. Therefore, it suggests that BMAL1 may also participate in the process of myocardial injury induced by sepsis by regulating mitochondrial autophagy.

Research has found that BMAL1 can positively regulate the expression of sirtuin 1 (SIRT1), the silent information regulator factor 2 related enzyme, thereby contributing to its biological function [20]. SIRT1 is a transcriptional regulator possessing histone deacetylase activity, involved in glycolysis and lipid metabolism regulation, cell cycle control, inflammation and oxidative stress suppression. Meanwhile, it also was closely associated with the development and progression of many cardiovascular diseases. Several studies have confirmed its involvement in myocardial dysfunction in sepsis. Han et al. found that specifically silencing the SIRT1 gene in the heart could reduce the survival rate of sepsis mice, exacerbate myocardial damage, and impair function [21]. Jiang et al. also demonstrated that activating the SIRT1 signaling pathway could increase the survival rate of sepsis mice and attenuate the cardiac damage induced by LPS [22]. These findings suggest that mitochondrial autophagy regulated by SIRT1 could protect kidney function. Therefore, we speculate that SIRT1 may also participate in the pathological process of myocardial injury in sepsis through mitochondrial autophagy. We aimed to investigate the regulatory role of BMAL1 in SIRT1-mediated mitochondrial autophagy and its mechanism of action on myocardial injury in sepsis through cell and animal experiments.