A PANoptosis Mechanism in Myocardial Ischemia-Reperfusion-Induced Injury: A Preliminary Exploration.

INTRODUCTION: Myocardial ischemia-reperfusion injury (MIRI) remains a critical clinical challenge. Evidence indicates that programmed cell death (PCD) contributes substantially to MIRI. This study evaluated the potential role of PANoptosis, a synergistic cell death mode integrating pyroptosis, apoptosis, and necroptosis, in MIRI. METHODS: Publications were retrieved from Web of Science, PubMed, and Scopus (cutoff February 27, 2024). Eligible studies used animal, cardiomyocyte, or other cardiac-resident cell models of ischemia/reperfusion and detected at least two PCD markers. Non-cardiac cells and incomplete injury models were excluded. RESULTS: Twenty-eight eligible studies were included. Pyroptosis, apoptosis, and necroptosis were synchronously activated in MIRI models, consistent with PANoptosis. Components of the PANoptosome (the multiprotein complex that executes PANoptosis), including NLRP3 (NLR family pyrin domain containing 3), ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), caspase-1 (CASP-1), caspase-8 (CASP-8), and receptor-interacting protein kinases 1 and 3 (RIPK1 and RIPK3), were upregulated. Oxidative stress and inflammatory cytokines served as upstream triggers of PANoptosome assembly, with RIPK3 mediating crosstalk among the three pathways. DISCUSSION: PANoptosis is a coordinated inflammatory cell death program central to MIRI. Concurrent activation and crosstalk of the three pathways imply that single-pathway interventions cannot achieve optimal cardioprotection. The PANoptosome may therefore serve as a multitarget therapeutic node. All evidence derives from cellular and animal studies; validation in human specimens is essential. CONCLUSION: This study demonstrates PANoptosis in MIRI and clarifies its molecular basis and therapeutic potential. Future work should validate these findings in human specimens and define the precise regulatory mechanisms involved.