Acute myocardial infarction (AMI) is typically triggered by sudden coronary artery occlusion resulting in ischemic necrosis of the corresponding myocardium due to insufficient blood supply [1]. Prolonged myocardial ischemia can lead to structural and functional abnormalities in heart, which can progress to heart failure and ultimately culminate in sudden cardiac death [2,3]. While advancements in treatment methods such as venous thrombolysis and percutaneous coronary intervention have significantly reduced the mortality rate of AMI, there has been a noticeable increase in the risk of post-MI heart failure [4]. Timely and effective diagnosis and treatment of AMI patients can significantly improve therapeutic outcomes and enhance patient survival rates. In clinical practice, CK-MB and cardiac troponins are widely utilized as valuable indictors for diagnosing AMI [5,6], but they are challenged by lack of specificity [7,8]. Therefore, further exploration of drugs that can shield against AMI-induced myocardial injury holds significant promise. Additionally, the search for novel and specific early diagnostic biomarkers for AMI can guide precise diagnosis of the condition.

The development of AMI is widely recognized to involve oxidative stress, inflammation, and subsequent cardiomyocyte apoptosis. During AMI, a robust inflammatory process is essential for effective myocardial injury healing. However, it can also give rise to an overabundance of damage and disruption in ventricular remodeling, eventually leading to the manifestation of heart failure and compromised myocardial function [9]. Research indicates that the nuclear factor-κB signaling pathway plays a pivotal role in the inflammatory injury of AMI, with its activation triggering the production of various proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6 [10]. Leukocytes are drawn into the injured myocardium following the release of multiple inflammatory factors, which further worsens oxidative stress and inflammatory damage.

Emerging evidence suggests that the pathophysiological process of myocardial ischemia or death in AMI is significantly influenced by oxidative stress, induced by an excess of reactive oxygen species (ROS) [11]. The overproduction of ROS disrupts the redox state balance and triggers cell apoptosis, ultimately exacerbating myocardial injury and worsening cardiac function [12]. It is important to highlight that oxidative stress also directly promotes the expression of inflammatory cytokines and inducing leukocyte chemotaxis, thus intensitying the inflammatory process [13]. In addition, oxidative stress is the primary factor contributing to the unfavorable prognosis associated with myocardial damage induced by AMI [14]. Apoptosis is also a key pathologic feature of AMI and contributes to cardiomyocyte cell injury [15]. Further, apoptosis is considered the primary cause responsible for myocardial cell loss following AMI, and it is strongly linked to ventricular remodeling and the subsequent development of heart failure [16,17]. Therefore, these studies lay a foundation for therapeutically targeting inflammation, oxidative stress and apoptosis as an effective strategy to mitigate AMI-induced cardiac injury.

Myocardial injury resulting from AMI is predominantly attributed to the demise of terminally differentiated cardiomyocytes [17]. Pyroptosis is a newly recognized inflammatory form of programmed cell death that commonly occurs in the presence of inflammatory conditions [18]. The hallmark features of pyroptosis comprise the activation of inflammasome, the cleavage of gasdermin-D (GSDMD), and the subsequent formation of membrane pores [19,20]. Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome initiates self‐cleavage of pro-caspase1, and activated caspase1 cleaves GSDMD to generate the N-terminal fragments of GSDMD (GSDMD-NT) that trigged membrane pore formation, eventually leads to the unleashing of inflammatory factors, loss of membrane integrity, and pyroptosis [21,22]. Pyroptosis, as an essential component of the body's innate immune defense system, assumes a pivotal function in safeguarding against infectious agents [23]. However, excessive pyroptosis have detrimental effects on the host [24]. Numerous studies have demonstrated that pyroptosis is an irreplaceable signaling cascade contributing to myocardial cell death [25,26]. Nonetheless, the functions of cardiomyocytes pyroptosis, its potential relationship with AMI, and the underlying molecular mechanisms remain largely elusive.

This study sought to investigate the influence of pyroptosis on myocardial injury following hypoxia and evaluate whether the implicated mechanisms are associated with alternations in myocardial inflammation, oxidative stress and apoptosis induced by acute myocardial hypoxia. Additionally, given the release of GSDMD from pyroptotic cardiomyocytes [27], we hypothesized that it holds promise as a potential diagnostic biomarker for AMI.