Cardiovascular diseases are the leading cause of death worldwide, posing significant healthcare difficulties, particularly in poorer countries where they account for 40 % of all deaths.1, 2, 3 A number of factors influence cardiovascular pathology rates, but as life expectancy rises, aging and chronic illnesses become more important.4 According to projections, by 2030, people 65 and older will make up almost one-fifth of the population, and cardiovascular deaths will account for 40 % of these deaths, making them the leading cause of death.5 Chronic conditions like diabetes and high blood pressure are major contributors to both new and existing cardiovascular disease, and the situation is getting worse as a result of population growth, demographic aging, and bad lifestyle choices.6,7 This medical difficulty is further exacerbated by improper treatment, poor therapeutic intervention, or inadequate detection of chronic health conditions.8 As a result, creating effective intervention objectives is essential for managing cardiovascular disease and lowering risk. Circular RNAs (circRNAs) are a special class of non-coding RNA molecules that have a continuous closed-loop structure as their structural feature. The 5′ cap and 3′-terminal portions of the precursor RNA are involved in back-splicing mechanisms that produce this structure. CircRNAs were first discovered in the 1970s,9 but the scientific community mostly ignored them and thought they were the result of mistaken "mis-splicing" or "scrambled splicing" occurrences.10 Modern sequencing techniques allowed scientists to detect large amounts of circRNAs in mammalian tissues, such as human, mouse, rat, porcine, and primate samples, in the second decade of the twenty-first century. To date, databases have identified >140,790 different circRNA molecules in human tissues and cellular systems.11

Doxorubicin (DOX), epirubicin, daunorubicin, and idarubicin are among the anthracycline (ANT) chemicals that have been essential anticancer medicines in clinical oncology for over 50 years.12 The foundation of treatment regimens for a wide range of cancers in children and adolescents, such as leukemias, small-cell lung cancers, lymphomas, breast cancers, Ewing sarcomas, and carcinomas of the bladder, esophagus, stomach, and liver, is these drugs.13,14 DOX uses multiple molecular routes to achieve its anticancer actions. Its ability to reversibly intercalate across DNA strands, creating connections through hydrogen bonds and van der Waals interactions, is one of the primary mechanisms.15,16 Moreover, formaldehyde-mediated interactions allow DOX to create covalent DNA bonds.17 Its stabilization of topoisomerase IIα (Top2α), an enzyme primarily expressed in rapidly growing cells, is another critical method. By switching between relaxed and supercoiled forms, Top2 alters DNA topology, causing DNA strand breaks and preventing RNA transcription and DNA replication.18,19 The antineoplastic action of DOX may be attributed to the production of free radicals.20,21 It is yet unclear how much each of these different processes contributes to the various forms of cancer. ANTs have dose-related organ toxicity despite their therapeutic benefits, with cardiac damage being the most notable. Clinical manifestations of this cardiotoxicity include arrhythmias, ischemic heart disease, dilated cardiomyopathy (DCM) with compromised systolic and diastolic function, or inflammatory diseases such as myocarditis and pericarditis.22,23 Ventricular enlargement and a decreased left ventricular ejection fraction (LVEF) are hallmarks of DCM, an irreversible cardiac structural change (Fig. 1).

There are no effective pharmaceutical treatments for this potentially fatal heart disease. When specific cumulative ANT doses are exceeded, the risk of developing delayed heart failure increases significantly: 200–3000 mg/m² for aclarubicin, 600 mg/m² for daunorubicin, 1000 mg/m² for epirubicin, 1900 mg/m² for esorubicin, 550 mg/m² for DOX (which is reduced to 450 mg/m² in patients receiving radiation therapy or with additional risk factors), and 160 mg/m² for mitoxantrone.24,25

DOX continues to be the most commonly used ANT in clinical settings. Cumulative DOX exposure is the main factor influencing the frequency of DCM. When cumulative dosages exceed 650 mg/m2, the incidence of DCM surpasses 35 %. Although even relatively modest cumulative doses of 200–360 mg/m² cannot eliminate cardiomyopathy risk, lowering the cumulative exposure to 400 mg/m² reduces the risk to about 5 %.26, 27, 28 Unintentional cytotoxic effects of DOX on cardiac myocytes might potentially result in delayed cardiac failure.29

Recent investigations have revealed that circRNAs directly modulate doxorubicin-induced cardiac injury through molecular mechanisms encompassing competitive endogenous RNA activity and protein interaction networks. Furthermore, circRNAs potentially influence doxorubicin cardiotoxicity by regulating cellular processes, including oxidative stress, programmed cell death pathways, pyroptosis, autophagic flux, and iron-dependent cell death. This review delineates the biogenesis and functional repertoire of circRNAs, examines their association with doxorubicin-induced cardiac dysfunction, and synthesizes current knowledge regarding the molecular mechanisms and cellular processes through which circRNAs influence doxorubicin cardiotoxicity, thereby establishing a theoretical foundation for circRNAs-targeted diagnostic and therapeutic interventions.