THE MODERN PARADIGM OF REGULATED CELL DEATH IN MYOCARDIAL ISCHEMIA: METAL-DEPENDENT MECHANISMS, DISULFIDPTOSIS, AND IMMUNOGENIC CELL DESTRUCTION – A LITERATURE REVIEW WITH A SYSTEMATIZED SEARCH
DOI:
https://doi.org/10.32345/USMYJ.3(164).2026.139-153Keywords:
ferroptosis, cuproptosis, disulfidptosis, pyroptosis, NETosis, myocardial infarction, ischemia–reperfusion injuryAbstract
Introduction. Current understanding of the pathogenesis of myocardial infarction is based on recognition of the multimodal nature of cardiomyocyte death, extending beyond the classical binary “apoptosis–necrosis” model.
Aim. To systematize and critically analyze current data on the molecular mechanisms of ferroptosis, cuproptosis, disulfidptosis, pyroptosis, and NET-associated processes in the context of myocardial ischemia–reperfusion injury.
Materials and methods. The study was conducted as a systematized literature review, with a systematic search of publications in PubMed, MEDLINE, Embase, Google Scholar, Scopus, and Web of Science. The search included sources available as of April 2026.
Results. The analysis showed that ferroptosis is characterized by disruption of iron homeostasis, depletion of antioxidant defense systems, and accumulation of lipid peroxidation products, whereas cuproptosis is associated with copper-dependent aggregation of lipoylated mitochondrial proteins and the development of proteotoxic stress. However, the clinical role of cuproptosis in myocardial infarction remains insufficiently validated. Disulfidptosis is considered a novel redox-dependent mechanism of cell death associated with NADPH depletion and disruption of the actin cytoskeleton; however, most available evidence has been obtained from non-cardiac experimental models. Pyroptosis is mediated predominantly through the NLRP3/caspase-1/GSDMD-dependent cascade and contributes to the amplification of the sterile inflammatory response. Excessive formation of neutrophil extracellular traps is associated with immunothrombosis, microvascular obstruction, and the “no-reflow” phenomenon.
Conclusions. The available evidence indicates that myocardial ischemia–reperfusion injury results from the interplay of metabolic, redox-dependent, and immunoinflammatory mechanisms, although their relative contributions and clinical significance vary substantially. Promising directions for further research include the validation of specific biomarkers, clarification of the role of novel forms of regulated cell death in the human myocardium, and evaluation of the potential of multitarget cardioprotection.
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