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AIM This study aimed to investigate the regulatory role of differentially-expressed circular RNAs (circRNAs) in mouse cardiomyocytes during doxorubicin (DOX)-induced cardiotoxicity. MAIN METHODS Two groups of mice were injected with equal volumes (0.1 mL) of normal saline and DOX. Mouse heart tissue was isolated and digested for total RNA extraction and then subjected to next-generation RNA-sequencing. Expression profiles of circRNAs and circRNA-miRNA-mRNA networks were also constructed. Overall, 48 upregulated and 16 downregulated circRNAs were found to be statistically significant (p < 0.05) in the DOX-injected group. Bioinformatics analysis revealed several potential biological pathways that might be related to apoptosis caused by DOX-induced cardiotoxicity. In addition, using qRT-PCR, we found that a circRNA coded by the Arhgap12 gene, termed circArhgap12, was upregulated in the mouse heart tissue upon DOX intervention. CircArhgap12 enhanced apoptotic cell rate, as assessed using terminal-deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay, and increased reactive oxygen species and malondialdehyde release as well as superoxide dismutase and caspase-3 activation. Using a luciferase reporter assay, we found that circArhgap12 could sponge miR-135a-5p. In rat primary cardiomyocytes, we found that si-circArhgap12 promoted apoptosis and oxidative stress by sponging the miR-135a-5p inhibitor. Using bioinformatics analysis and luciferase reporter assay, we found that miR-135a-5p might have a potential target site for ADCY1 mRNA. KEY FINDINGS Our research demonstrated that the expression profile of circRNAs was modified significantly and that circArhgap12 might play a competitive role among endogenous RNAs in mouse cardiomyocytes during DOX-induced cardiotoxicity. SIGNIFICANCE Our study may provide a preliminary understanding of DOX-induced cardiotoxicity modulated by circRNA and its competing endogenous RNAs network.