Circular RNAs in Cardiovascular Diseases: From Regulatory Networks to Functional Effectors.

Circular RNAs have emerged as important regulators of gene expression in cardiovascular disease, expanding the current understanding of the molecular mechanisms that underlie cardiac remodeling and dysfunction. Initially regarded as byproducts of aberrant splicing, circRNAs are now recognized as stable, abundant, and functionally versatile molecules with marked tissue specificity and diverse modes of action. In the cardiovascular system, circRNAs are generated through tightly regulated back-splicing mechanisms and act through multiple molecular pathways, including microRNA sequestration, protein scaffolding, modulation of transcription and splicing, regulation of mitochondrial and metabolic homeostasis, and in some cases, peptide translation. These properties position circRNAs as regulatory hubs that connect molecular interactions to functional cellular outcomes. Across a broad range of cardiovascular conditions, including heart failure, myocardial ischemia, fibrosis, arrhythmias, cardiotoxicity, and cardiorenal syndrome, circRNAs have been implicated in processes such as hypertrophy, inflammation, cell death, extracellular matrix remodeling, and regenerative responses. Beyond their mechanistic relevance, circRNAs also hold preclinical relevance as circulating biomarkers and therapeutic targets owing to their stability in biofluids and their capacity to modulate disease-relevant networks. Nevertheless, major challenges remain, including incomplete functional validation, methodological heterogeneity, annotation inconsistencies, and barriers to clinical translation. In this review, we synthesize the current knowledge on circRNA biogenesis, molecular function, disease-specific roles, biomarker potential, and therapeutic applications and discuss the conceptual and technical advances required to move the field from descriptive association toward mechanistic and clinical impact.