Aprocitentan mitigates doxorubicin-induced cardiotoxicity by inhibiting cuproptosis, oxidative stress, and mitochondrial impairments via the activation of sirtuin 7

Doxorubicin (DOX) is a widely used chemotherapy drug for Cancer while leads to several cardiac disorders including cardiomyopathy and heart failure. Aprocitentan is a novel dual endothelin-1 receptor antagonist and functions as an effective antihypertensive drug for resistant hypertension. However, the exact roles of aprocitentan in DOX-induced cardiotoxicity remains largely unclear.In this work, we explored potential participants of aprocitentan in DOX-induced cardiotoxicity. Mice were treated with DOX to induce cardiotoxicity, and then received either aprocitentan or tetrathiomolybdate interventions respectively. Compared with controls, DOX-treated mice exhibited cardiac impairments and dysfunction. Notably, aprocitentan or tetrathiomolybdate intervention remarkably mitigated DOX-mediated cardiac cardiotoxicity, as evidenced by alleviated myocardial fibrosis and improved cardiac function. Furthermore, aprocitentan or tetrathiomolybdate administration significantly mitigated myocardial Cuproptosis, oxidative stress, cardiac aging and inflammation in DOX-treated mice with decreased levels of DLAT accumulation, as well as downregulated expressions of HSP70, P16 and P21, respectively. In cultured primary rat cardiomyocytes, treatment with aprocitentan alleviated DOX-induced augmentation of Cuproptosis and oxidative stress with reduced DLAT accumulation. Moreover, aprocitentan administration strikingly reversed DOX-induced and elesclomol-aggravated cellular senescence and mitochondrial injury in cardiomyocytes. More importantly, knock-down of Sirtuin 7 (SIRT7) by SIRT7 siRNA blocked the beneficial effects of aprocitentan on DOX-associated Cuproptosis, oxidative stress, mitochondrial injury, and senescence in cardiomyocytes. In summary, aprocitentan exerts as a novel therapeutic agent for alleviation of DOX-induced cardiotoxicity through the inhibition of Cuproptosis, oxidative stress, cardiac aging and mitochondrial injuries via the activation of SIRT7, offering new possibilities for prevention and treatment of DOX-induced cardiac disorders.