Circular RNAs in Drug-Induced Cardiotoxicity: Roles, Mechanisms, and Therapeutic Potential.

Drug-induced cardiotoxicity (DIC) remains a major challenge in drug development and clinical practice, often resulting in treatment interruption, drug attrition, and adverse cardiovascular outcomes. DIC has been associated with a wide range of therapeutic agents, including anthracyclines, HER2-targeted therapies, tyrosine kinase inhibitors, immune checkpoint inhibitors, and other cardiotoxic drugs. Circular RNAs (circRNAs) have attracted increasing attention as stable and versatile regulatory RNAs involved in cardiovascular injury. This review summarizes the biogenesis and functional mechanisms of circRNAs, their pathological roles in DIC, biomarker potential, therapeutic implications, and translational challenges. CircRNAs regulate gene expression through diverse mechanisms, including miRNA sequestration, interactions with RNA-binding proteins, transcriptional regulation, modulation of alternative splicing, and, in some cases, peptide translation. These regulatory functions have been implicated in apoptosis, oxidative stress, mitochondrial dysfunction, inflammatory signaling, pyroptosis, and cardiac remodeling during DIC. Emerging evidence suggests that circRNAs may serve as candidate molecular markers and potential therapeutic targets for DIC. However, the current evidence is derived predominantly from cellular and animal models, with doxorubicin-induced cardiotoxicity accounting for a substantial proportion of available studies. Clinical validation, particularly in well-characterized patient cohorts and across different drug classes, remains limited. Overall, further efforts are needed to establish standardized circRNA detection and quantification methods, validate their functional roles, conduct prospective clinical studies, and determine their incremental value in combination with established cardiac biomarkers before circRNA-based approaches can be translated into clinical management of DIC.