Mechanisms and Therapeutic Potential of Multiple Forms of Cell Death in Myocardial Ischemia-Reperfusion Injury

Programmed cell death, especially programmed necrosis such as necroptosis, ferroptosis, and pyroptosis, has attracted significant attention recently. Traditionally, necrosis was thought to occur accidentally without signaling pathways, but recent discoveries have revealed that molecular pathways regulate certain forms of necrosis, similar to apoptosis. Accumulating evidence indicates that programmed necrosis is involved in the development of various diseases, including myocardial ischemia-reperfusion injury (MIRI). MIRI occurs when blood flow and oxygen return to an ischemic area, causing excessive production of reactive oxygen species. While this reperfusion is critical for treating myocardial infarction, it inevitably causes cellular damage via oxidative stress. Furthermore, this cellular damage triggers multiple forms of cardiomyocyte death, which is the primary cause of inflammation, cardiac tissue remodeling, and ensuing heart failure. Therefore, understanding the molecular mechanisms of various forms of cell death in MIRI is crucial for therapeutic target discovery. Developing therapeutic strategies to inhibit multiple cell death pathways simultaneously could provide effective protection against MIRI. In this paper, we review the fundamental molecular pathways and MIRI-specific mechanisms of apoptosis, necroptosis, ferroptosis, and pyroptosis. Additionally, we suggest that the simultaneous suppression of multiple cell death pathways could be an effective therapy and identify potential therapeutic targets for implementing this strategy.