The emerging role of circular RNAs in acute and chronic heart failure: mechanisms, biomarkers, and therapeutic potential

Abstract

Circular RNAs (circRNAs) are covalently closed non-coding RNAs with diverse regulatory functions, high stability, and tissue specificity. This review examines their biogenesis, molecular mechanisms, experimental evidence, biomarker potential, and therapeutic implications in acute heart failure and chronic heart failure. By functioning as microRNA sponges, interacting with RNA-binding proteins, acting as protein scaffolds, undergoing cap-independent translation, and participating in stress-response signaling, circRNAs may regulate heart failure progression. Representative circRNAs, including circHIPK3, circSIRT1, circSLC8A1, circRNA-00203, and HRCR, have been linked to cardiomyocyte injury, calcium homeostasis, apoptosis, hypertrophy, fibrosis, inflammation, and ventricular remodeling. Circulating and exosome-derived circRNAs may also serve as biomarkers for diagnosis, prognosis, and disease monitoring. However, clinical translation remains limited by challenges in detection and standardization, low transcript abundance, tissue and cell heterogeneity, delivery efficiency, off-target effects, immunogenicity, and insufficient validation in large clinical cohorts. Most available evidence comes from preclinical models of myocardial infarction, pressure overload, and cardiac remodeling; evidence in heart failure with preserved ejection fraction , heart failure with mildly reduced ejection fraction, and large human populations remains limited. Overall, circRNAs provide new insights into heart failure pathophysiology and represent promising candidates for biomarker development and targeted therapy, but rigorous clinical validation is required before routine application.