Reshaping the ncRNA Regulatory Network: Decoding the Pathological Mechanisms and Novel Therapeutic Paradigms of Heart Failure

Heart failure (HF) is a significant global health issue, and its complicated pathogenesis needs to be further clarified. In recent years, non-coding RNAs (ncRNAs) have emerged as key players in the development and pathogenesis of HF; nonetheless, their systemic regulatory networks and clinical translational capacity need to be further explored. This review briefly summarizes available evidence on the roles and mechanisms of microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in HF, centering on their molecular functions in regulating HF via modulating the main pathological processes including cardiac inflammation, apoptosis, cardiac hypertrophy, and myocardial fibrosis (MF). We highlight the promise of ncRNAs as a class of promising biomarkers and therapeutic targets, and summarize four major categories of ncRNA-targeted intervention strategies, including nucleic acid oligonucleotide drugs, conventional cardiovascular chemical agents, natural plant extracts, and standardized exercise regimens. We suggest that "modulating the network of ncRNA regulation" can be a new direction to conquer the challenges associated with monotherapies. Meanwhile, we conduct a detailed dissection of diverse delivery vehicles for ncRNA-targeted drugs and thoroughly discuss the technical bottlenecks hindering their clinical translation. Furthermore, framing ncRNAs and their interactive partners as a dynamic ecosystem allows the characterization of stage-specific remodeling of ncRNA regulatory networks throughout HF progression from compensation to decompensation. A full grasp of HF heterogeneity is thereby achievable, further emphasizing the necessity of advancing ncRNA profile-guided precision therapeutics. However, attention should be paid to the spatiotemporal dynamics of ncRNAs and intercellular communication in future research, and the translation of ncRNAs into clinical application with multidisciplinary collaboration among cardiology, RNA biology, and nanomedicine will need further acceleration.