Targeting non-coding RNAs and alarmins in myocardial ischemia-reperfusion injury: emerging molecular therapeutics for...

Myocardial ischemia-reperfusion injury (MIRI) remains a major unresolved cause of perioperative myocardial dysfunction after coronary artery bypass grafting, valve surgery requiring cardiopulmonary bypass, heart transplantation, and other procedures involving controlled ischemia followed by reperfusion. Reperfusion is essential for tissue salvage, yet it initiates mitochondrial reactive oxygen species generation, calcium overload, mitochondrial permeability transition pore opening, endothelial dysfunction, sterile inflammation, microvascular obstruction, arrhythmogenesis, and regulated cardiomyocyte death. This review provides an updated conceptual synthesis of the current framework of MIRI around two interacting molecular layers: non-coding RNAs (ncRNAs) and alarmins, also known as damage-associated molecular patterns. MicroRNAs, long non-coding RNAs, and circular RNAs regulate apoptosis, autophagy, pyroptosis, ferroptosis, angiogenesis, fibrosis, and macrophage polarization through post-transcriptional repression, competing endogenous RNA networks, and epigenetic scaffolding. In parallel, alarmins such as high-mobility group box 1 (HMGB1), S100 proteins, extracellular histones, mitochondrial DNA, and interleukin-33 link tissue injury to innate immune activation through Toll-like receptors, RAGE, inflammasome pathways, and ST2-dependent cardioprotective signaling. Mechanistic crosstalk, exemplified by the MALAT1/miR-200c/HMGB1 axis and the interaction between HMGB1 antagonism and miR-21-dependent survival signaling, provides a rationale for multi-target cardioprotection rather than single-pathway blockade. Translational progress is ongoing but remains in early stages. Although antisense oligonucleotides, small interfering RNAs, mRNA therapeutics, biomimetic nanoparticles, exosome-based delivery, and local perioperative administration through cardioplegia or epicardial injection provide potential translational routes, no ncRNA- or alarmin-directed therapy is currently established for routine prevention of surgical MIRI.