Authors: Anna Nowak-Szwed, Ceren Eyileten, Zofia Wicik, Sara Ahmadova, Dirk von Lewinski, Harald Sourij & Marek Postula. DOI: https://doi.org/10.1007/s10557-026-07860-z

Abstract

Myocardial ischemia/reperfusion (I/R) injury contributes significantly to post-infarction cardiac dysfunction and heart failure, despite advances in reperfusion therapies. Among molecular regulators of I/R injury, sirtuins (SIRTs) play key roles in modulating oxidative stress, apoptosis, inflammation, and mitochondrial function. Increasing evidence highlights the regulatory role of non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in controlling sirtuin signaling in the ischemic myocardium. This review synthesizes current preclinical findings on miRNA- and lncRNA-mediated regulation of SIRTs in myocardial I/R injury model. It further highlights the emerging mechanistic pathways through which ncRNAs influence sirtuin activity and discusses their potential relevance as therapeutic targets. Several miRNAs aggravate cardiomyocyte damage by downregulating SIRTs, while lncRNAs exert protective effects through miRNA sponging and sirtuin upregulation. These regulatory axes influence key cellular processes, including mitochondrial homeostasis, pyroptosis, apoptotic signaling and regulation of the inflammasome pathways. Additionally, the network analysis identified apoptosis as the most frequently involved process, with SIRT1 and miR-29a, miR-34a, and miR-217-5p showing the highest degree of connectivity. Despite growing mechanistic insight, translation into clinical practice is hindered by the scarcity of human studies and randomized trials. Moreover, current knowledge regarding miRNAs is limited to only three sirtuin isoforms, underscoring the need for further investigation. Understanding the ncRNA–SIRT axis may offer novel therapeutic strategies for mitigating myocardial I/R injury.