2. Academic Validation
  3. Inhibiting mir-34a-5p regulates doxorubicin-induced autophagy disorder and alleviates myocardial pyroptosis by targeting Sirt3-AMPK pathway

Inhibiting mir-34a-5p regulates doxorubicin-induced autophagy disorder and alleviates myocardial pyroptosis by targeting Sirt3-AMPK pathway

  • Biomed Pharmacother. 2023 Oct 6:168:115654. doi: 10.1016/j.biopha.2023.115654.
Zuoquan Zhong 1,  Yefei Gao 2,  Jiedong Zhou 2,  Fang Wang 3,  Peipei Zhang 4,  Songqing Hu 5,  Haowei Wu 5,  Haifei Lou 4,  Jufang Chi 6,  Hui Lin 7,  Hangyuan Guo 8
Affiliations

Affiliations

  • 1 The First Clinical Medical College, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China; School of Medicine, Shaoxing University, Shaoxing, China; Department of Cardiology, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing 312000, Zhejiang, China.
  • 2 School of Medicine, Shaoxing University, Shaoxing, China.
  • 3 The First Clinical Medical College, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.
  • 4 Zhejiang Chinese Medical University, Hangzhou, China.
  • 5 Zhejiang University School of Medicine, Hangzhou, China.
  • 6 Department of Cardiology, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing 312000, Zhejiang, China.
  • 7 Department of Cardiology, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing 312000, Zhejiang, China; Healthy Science Center, The Affiliated Lihuili Hospital of Ningbo University, Ningbo University, Ningbo, Zhejiang 315211, China. Electronic address: 122525790@qq.com.
  • 8 The First Clinical Medical College, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China; School of Medicine, Shaoxing University, Shaoxing, China; Department of Cardiology, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing 312000, Zhejiang, China. Electronic address: guohy@usx.edu.cn.
PMID: 37806095 DOI: 10.1016/j.biopha.2023.115654
Abstract

Doxorubicin (DOX) is a commonly used chemotherapy drug widely applied in various cancers such as breast Cancer, leukemia, and sarcomas. However, its usage is limited by cardiotoxicity. Additionally, the cardiac toxicity of DOX accumulates with dose and duration, making it imperative to identify therapeutic targets for DOX-induced cardiomyopathy (DIC). It has been reported that miRNAs are involved in the progression of DIC. Mir-34a-5p has been identified as an early diagnostic marker for DIC. While studies have shown the involvement of mir-34a-5p in DIC Apoptosis, it has not been validated in animal models, nor has the potential improvement of DIC by inhibiting mir-34a-5p been confirmed. Autophagy and Pyroptosis are key factors in the development of DIC and can serve as therapeutic targets for its treatment. In this study, we found that mir-34a-5p was upregulated in the heart after DOX treatment and that the inhibition of mir-34-5p reduced Autophagy and Pyroptosis in DIC. We also found that the inhibition of mir-34a-5p inhibited Pyroptosis by regulating Autophagy and reducing mitochondrial Reactive Oxygen Species. Moreover, we identified Sirtuin3 (SIRT3) as a target gene of mir-34a-5p using a double-luciferase reporter assay. overexpression SIRT3 reduced Pyroptosis by alleviating Autophagy. Our research findings suggest that inhibiting mir-34a-5p has a beneficial role in alleviating Autophagy and Pyroptosis in DIC. This provides therapeutic prospects for treating DIC.

Keywords

Autophagy; Doxorubicin-induced cardiotoxicity; Mir-34a-5p; Pyroptosis; Sirt3.

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