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Novel GSDMD inhibitor GI-Y1 protects heart against pyroptosis and ischemia/reperfusion injury by blocking pyroptotic pore formation

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Abstract

Activation of gasdermin D (GSDMD) and its concomitant cardiomyocyte pyroptosis are critically involved in multiple cardiac pathological conditions. Pharmacological inhibition or gene knockout of GSDMD could protect cardiomyocyte from pyroptosis and dysfunction. Thus, seeking and developing highly potent GSDMD inhibitors probably provide an attractive strategy for treating diseases targeting GSDMD. Through structure-based virtual screening, pharmacological screening and subsequent pharmacological validations, we preliminarily identified GSDMD inhibitor Y1 (GI-Y1) as a selective GSDMD inhibitor with cardioprotective effects. Mechanistically, GI-Y1 binds to GSDMD and inhibits lipid- binding and pyroptotic pore formation of GSDMD-N by targeting the Arg7 residue. Importantly, we confirmed the cardioprotective effect of GI-Y1 on myocardial I/R injury and cardiac remodeling by targeting GSDMD. More extensively, GI-Y1 also inhibited the mitochondrial binding of GSDMD-N and its concomitant mitochondrial dysfunction. The findings of this study identified a new drug (GI-Y1) for the treatment of cardiac disorders by targeting GSDMD, and provide a new tool compound for pyroptosis research.

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Data availability

All the data in this study are available upon reasonable request from the corresponding author.

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Acknowledgements

We appreciate Professor Lufeng Hu from the Department of Pharmacy of First Affiliated Hospital of Wenzhou Medical University for his help in chromatographic analysis. We are grateful to Lingli Hou, Tongliang Huang, Yanni Dong, Jiansong Lin and Mengxin Zhang from the scientific research center of Wenzhou Medical University for their help in echocardiography and immunofluorescence experiment.

Funding

This study was supported by the National Natural Science Foundation of China (No. 82003750 to B.Z. Ye, No. 82202380 to S.S. Dai, No. 82070446 to W.J. Huang), Zhejiang Provincial Natural Science Foundation of China (No. LQ21H020009 to B.Z. Ye, No. LQ23H310005 to S.S. Dai, No. LGD21H020003 to J.B. Han, No. LY22H02004 to Z.Q. Huang), the Key Research and Development Program of Zhejiang (No.2019C03012 to W.J. Huang), Zhejiang Provincial Health Bureau Science Foundation (No. 2022RC046 to S.S. Dai), Wenzhou Science and Technology Bureau (No. Y20220082 to S.S. Dai) and Zhejiang Provincial Science and Technology Innovation Program (New Young Talent Program) for College Students (No. 2022R413C081 to L.F. Zhong).

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  1. Lingfeng Zhong, Jibo Han and Xiaoxi Fan contributed equally to this paper.

Authors and Affiliations

  1. Department of Cardiology and The Key Laboratory of Cardiovascular Disease of Wenzhou, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China

    Lingfeng Zhong, Xiaoxi Fan, Zhouqing Huang, Lan Su, Xueli Cai, Shuang Lin, Xudong Chen, Weijian Huang & Bozhi Ye

  2. Department of Cardiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China

    Jibo Han

  3. The Key Laboratory of Emergency and Disaster Medicine of Wenzhou, Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Shanshan Dai

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  1. Lingfeng Zhong
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Correspondence to Weijian Huang, Shanshan Dai or Bozhi Ye.

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Zhong, L., Han, J., Fan, X. et al. Novel GSDMD inhibitor GI-Y1 protects heart against pyroptosis and ischemia/reperfusion injury by blocking pyroptotic pore formation. Basic Res Cardiol 118, 40 (2023). https://doi.org/10.1007/s00395-023-01010-4

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