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

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

  • Int Immunopharmacol. 2025 Feb 20:148:114141. doi: 10.1016/j.intimp.2025.114141.
Yu-Fei Chen 1,  Rui-Qiang Qi 1,  Lin Zhao 2,  Li-Rong Liang 3,  Jia-Wei Song 1,  Xin-Yu Zhou 1,  Yi-Hang Chen 4,  Si-Yuan Wang 1,  Qi Wang 4,  Ying Liu 1,  Ying Dong 4,  Xiao-Yan Liu 4,  Jing Li 4,  Jiu-Chang Zhong 5
Affiliations

Affiliations

  • 1 Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University. Beijing 100020 China; Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020 China.
  • 2 Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020 China.
  • 3 Medical Research Center, Beijing Chaoyang Hospital and Beijing Institute of Respiratory Medicine, Capital Medical University, Beijing 100020 China.
  • 4 Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University. Beijing 100020 China.
  • 5 Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University. Beijing 100020 China; Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020 China. Electronic address: jczhong@sina.com.
PMID: 39930646 DOI: 10.1016/j.intimp.2025.114141
Abstract

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.

Keywords

Aprocitentan; Cuproptosis; Doxorubicin-induced cardiotoxicity; Oxidative stress; Sirtuin 7.

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