Targeting Non-Coding RNAs and Alarmins in Myocardial Ischemia-Reperfusion Injury: Emerging Molecular Therapeutics in Cardiothoracic Surgery

Myocardial ischemia-reperfusion (I/R) injury represents a major clinical challenge in cardiothoracic surgery, notably during cardiopulmonary bypass, coronary artery bypass grafting (CABG), and orthotopic heart transplantation. The complex pathophysiology underlying I/R injury involves severe disruptions in protein dynamics, pronounced inflammatory cascades, and the induction of cellular apoptosis. Emerging molecular evidence highlights the critical regulatory roles of non-coding RNAs (ncRNAs)—specifically microRNAs (miRNAs) and long non-coding RNAs (lncRNAs)—alongside damage-associated molecular patterns (DAMPs), or alarmins, in orchestrating these processes. This review provides a comprehensive analysis of the molecular interplay between ncRNAs and alarmins during myocardial I/R injury. It delineates how the dysregulation of these molecules alters proteostasis, amplifies oxidative stress, and initiates perioperative inflammatory pathways. Furthermore, we summarize recent preclinical and clinical findings that identify specific ncRNAs (e.g., miR-1, miR-21, and MALAT1) and alarmins (e.g., HMGB1) as viable, targeted therapeutic avenues. Modulating these targets offers a promising approach to mitigating myocardial damage, enhancing cardioprotection, and improving surgical outcomes. Future investigations must prioritize translating these molecular targets into clinically feasible cardioprotective strategies.