Potential Relationship Between Ferroptosis and Pyroptosis in Myocardial Ischemia/Reperfusion Injury: Molecular Mechanisms and Therapeutic Targets.

While restoring blood flow is the primary treatment for acute myocardial infarction (AMI), this process often triggers additional damage known as myocardial ischemia/reperfusion injury (MIRI). Recent studies have suggested that regulated cell death is a major contributor to cardiomyocyte injury during ischemia and subsequent reperfusion. Notably, emerging evidence has demonstrated that both ferroptosis and pyroptosis play important roles in the pathogenesis of MIRI. Ferroptosis is primarily driven by iron-dependent lipid peroxidation, whereas pyroptosis is characterized by inflammasome-mediated inflammatory cell death. However, these processes are typically studied independently, and their potential interactions and shared regulatory mechanisms remain unclear. In this review, we comprehensively summarize the molecular mechanisms underlying ferroptosis and pyroptosis in MIRI. We also discuss emerging evidence supporting the crosstalk between these two processes, with a particular focus on shared upstream triggers such as reactive oxygen species (ROS), mitochondrial dysfunction, and common regulatory proteins, including nuclear factor erythroid 2-related factor 2 (Nrf2), p53, and members of the high mobility group box (HMGB) family. Furthermore, we highlight current therapeutic strategies targeting ferroptosis and pyroptosis and explore the potential of dual-targeting approaches based on their shared signaling pathways. A deeper understanding of the interplay between these two forms of cell death may provide novel insights into the pathogenesis of MIRI and support the development of more effective cardioprotective strategies.