LncRNA–miRNA–mRNA Regulatory Axis in Cardiac Hypertrophy: Systems Biology Perspective

Background: Cardiac hypertrophy is a maladaptive response to chronic hemodynamic stress and a major precursor to heart failure, arrhythmias, and sudden cardiac death. While significant advances have been made in understanding transcriptional and signaling mechanisms, emerging evidence points to non-coding RNAs—particularly long non-coding RNAs (lncRNAs) and microRNAs (miRNAs)—as critical regulators of hypertrophic remodeling. The lncRNA–miRNA–mRNA axis forms a multilayered regulatory network that modulates gene expression through competitive binding, chromatin remodeling, and transcript stability. However, a comprehensive systems-level understanding of these interactions in the context of cardiac hypertrophy remains limited. Methods and Results: In this study, we employed integrated transcriptomic and bioinformatic analyses in pressure-overloaded murine hearts and patient-derived myocardial biopsies to map functional lncRNA–miRNA–mRNA circuits. Network topology analysis revealed several key regulatory axes, including lncRNA H19–miR-675–IGF1R and lncRNA CHRF–miR-489–Myd88, which modulate hypertrophic signaling, inflammation, and apoptosis. Co-expression and target prediction models were validated using luciferase assays, CRISPR-based perturbation, and RNA immunoprecipitation. Pathway enrichment identified convergent effects on MAPK, PI3K-AKT, and calcineurin-NFAT signaling cascades. Targeted inhibition of pro-hypertrophic nodes within these axes reversed cardiomyocyte enlargement and restored gene expression profiles in vitro. Conclusion: Our findings highlight the lncRNA–miRNA–mRNA regulatory axis as a central node in the epigenetic and post-transcriptional control of cardiac hypertrophy. Through systems biology modeling and multi-tier validation, this study identifies novel non-coding RNA circuits that can serve as biomarkers and therapeutic targets. These results expand the mechanistic landscape of cardiac remodeling and support the development of RNA-based precision interventions for hypertrophic heart disease.