2. Academic Validation
  3. Sulfiredoxin 1 ameliorates doxorubicin-induced cardiotoxicity by suppressing oxidative stress and inflammation via the Sirt1/NLRP3 pathway

Sulfiredoxin 1 ameliorates doxorubicin-induced cardiotoxicity by suppressing oxidative stress and inflammation via the Sirt1/NLRP3 pathway

  • Int Immunopharmacol. 2024 Nov 15:141:113010. doi: 10.1016/j.intimp.2024.113010.
Zhaoxia Zhang 1,  Tingsha Du 2,  Nan Wu 1,  Shuwen Yang 2,  Jian Wang 1,  Jianye Peng 3,  Zhenyu Jia 2,  Jiating Dai 2,  Xianfeng Du 1,  Mingjun Feng 1,  Huimin Chu 4,  Caijie Shen 5
Affiliations

Affiliations

  • 1 Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo 315000, China.
  • 2 Health Science Center, Ningbo University, Ningbo 315000, China.
  • 3 Department of Cardiovascular Medicine, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China. Electronic address: pengshu1234@163.com.
  • 4 Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo 315000, China. Electronic address: epnbheart@163.com.
  • 5 Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo 315000, China. Electronic address: shenzihai1101@126.com.
PMID: 39182271 DOI: 10.1016/j.intimp.2024.113010
Abstract

Background: Doxorubicin (DOX) is limited in clinical use due to its cardiotoxic side effects. Oxidative stress and inflammation are pivotal mechanisms underlying doxorubicin-induced cardiotoxicity (DIC). Sulfiredoxin 1 (Srxn1) plays a central role in antioxidant effects. However, the role of Srxn1 in DIC has not yet been fully elucidated. This study aims to explore the effects and underlying mechanisms of Srxn1 on DIC.

Methods: We overexpressed Srxn1 in the myocardium using an adeno-associated virus 9 (AAV9) system, delivered through tail vein injection. C57BL/6 mice received intraperitoneal injections of DOX (4 mg/kg) weekly for four consecutive weeks to establish a mouse model of DIC. We used echocardiography, histopathological, and molecular techniques to elucidate the effects and mechanisms.

Results: Our findings demonstrate that overexpression of Srxn1 significantly enhanced cardiac function and mitigated myocardial injury in mice exposed to DOX. Overexpressing Srxn1 attenuated oxidative stress and inflammation induced by DOX. Furthermore, Srxn1 overexpression led to upregulation of Sirtuin 1 (SIRT1) expression and inhibited the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome. Notably, the protective effects of Srxn1 were significantly abrogated by the SIRT1 Inhibitor EX527.

Conclusion: The protective effects of Srxn1 against DOX-induced cardiac oxidative stress and inflammation operate by targeting the SIRT1/NLRP3 signaling pathway to alleviate DIC. Srxn1 could be a potential candidate for the treatment of DOX-induced myocardial injury.

Keywords

Cardiotoxicity; Doxorubicin; Sulfiredoxin 1.

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