From multi-target to network synergy: A systematic review of how traditional Chinese medicine acts against myocardial ischemia-reperfusion injury via miRNA-mediated systemic communication

BACKGROUND: Myocardial ischemia-reperfusion injury (MIRI) refers to further damage to myocardial cells caused by multiple factors after blood flow is restored to the ischemic myocardium. Currently, there is a lack of effective treatment strategies in clinical practice. While microRNA (miRNA) is recognized as pivotal regulators, current therapeutic strategies rarely harness its network properties or systemic communicative roles. PURPOSE: To summarize how traditional Chinese medicine (TCM) employs multi-target mechanisms to modulate miRNA networks against MIRI, and to elucidate its systemic cardioprotective effects mediated by extracellular vesicle (EV)-carried miRNAs, thereby providing a rational framework for future drug development. METHODS: Following PRISMA guidelines, a systematic review of preclinical studies (2015-2025) from PubMed, Web of Science, CNKI, Wanfang, and VIP was conducted, focusing on miRNA-mediated mechanisms in MIRI. RESULTS: Analysis of 53 studies indicates that pharmacological agents-notably various TCM compounds-can coordinately regulate clusters of cardiac miRNAs (e.g., miR-21, miR-133) to synergistically attenuate apoptosis, oxidative stress, and inflammation. Beyond direct cardiac modulation, evidence also indicates that medicines can remotely affect the heart by altering the EV miRNAs secreted by cells in different tissues or organs. CONCLUSIONS: A two-tiered therapeutic framework is proposed: 1) network synergy targeting: simultaneously modulating interrelated miRNA hubs within the heart; and 2) systemic communication targeting: guiding EV miRNA cargo to restore systemic signaling. TCM research strongly supports this paradigm, offering a novel roadmap for developing MIRI therapeutics that combine direct cardiac repair with systemic crosstalk.