Cardiac Circ‐ZNF609 Inhibition Attenuates Doxorubicin‐Induced Cardiotoxicity Without Affecting the Chemotherapeutic Efficacy of Doxorubicin on Cancer in Female Mice

The cardiac burden associated with doxorubicin (DOX) significantly limits its application in cancer treatment. Therefore, it is essential to identify effective strategies to protect the heart from cardiotoxic damage caused by chemotherapy. As sex is among the risk factors associated with DOX-induced cardiotoxicity, whether the cardiac beneficial effects observed from male mice can be applied to female mice remains unknown. We established a two-week DOX-induced cardiotoxicity model, in which the cumulative DOX dose administered to mice was comparable to that used in previous research. This model effectively induces cardiotoxicity and fibrosis while allowing for a sufficiently long monitoring period to evaluate the chemotherapeutic effects of DOX on tumors, without imposing an excessive physiological burden on the mice from prolonged tumor growth. Utilizing this tumor-bearing murine model, we employed TC-1 cancer cells, which express HPV16-E6 and HPV16-E7 proteins, to investigate the cardioprotective effects of circ-ZNF609 inhibition in DOX-treated tumor-bearing female mice. Our findings indicate that cardiac inhibition of circ-ZNF609 protects against DOX-induced cardiotoxicity without compromising the anti-tumor efficacy of DOX in females. These results suggest that targeting circ-ZNF609 in the heart may represent a promising and viable therapeutic strategy for preventing DOX-induced cardiotoxicity.