Circular RNAs as Regulatory Mediators and Therapeutic Targets in Doxorubicin-Induced Cardiotoxicity.

Abstract

Doxorubicin (DOX) remains a cornerstone chemotherapeutic agent despite its dose-dependent cardiotoxicity that can progress to irreversible dilated cardiomyopathy. At the same time, the mechanisms of DOX-induced cardiac injury are multifactorial, emerging evidence highlights circular RNAs (circRNAs) a unique class of covalently closed non-coding RNA molecules, as critical regulators of DOX cardiotoxicity. This review comprehensively examines the biogenesis and functional repertoire of circRNAs and their pivotal role in modulating DOX-induced cardiac damage. CircRNAs exert cardioprotective or cardiotoxic effects primarily through competitive endogenous RNA activity, RNA-binding protein interactions, translational products, and RNA N6-adenosine methylation-related mechanisms. Notably, the research gap lies in understanding how circRNAs orchestrate the complex interplay between five major regulated cell death pathways triggered by DOX: apoptosis, autophagy, necroptosis, ferroptosis, and pyroptosis. Additionally, circRNAs influence cellular processes underlying DOX-induced cardiomyocyte dysfunction, including oxidative stress, calcium handling defects, myocardial atrophy, thrombosis, and premature senescence. The novelty of this review lies in synthesizing evidence on circRNA-mediated regulatory networks across these diverse pathophysiological mechanisms, providing a theoretical foundation for developing circRNA-based diagnostic biomarkers and therapeutic interventions. Future research directions should focus on elucidating additional molecular mechanisms, validating circRNA-based biomarkers, and establishing translational frameworks for clinical applications to mitigate DOX cardiotoxicity while preserving its antitumor efficacy.