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Serpina3k lactylation protects from cardiac ischemia reperfusion injury

Author

Listed:
  • Le Wang

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Peking University First Hospital)

  • Dandan Li

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Fang Yao

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Shenzhen)

  • Shanshan Feng

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Chao Tong

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Rongjia Rao

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Meiyan Zhong

    (Shenzhen)

  • Xianqiang Wang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Wei Feng

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Zhan Hu

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Bo Jin

    (Peking University First Hospital)

  • Li Wang

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Shenzhen)

  • Shengshou Hu

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Shenzhen
    Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Bingying Zhou

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Shenzhen)

Abstract

Lactate produced during ischemia-reperfusion injury is known to promote lactylation of proteins, which play controversial roles. By analyzing the lactylomes and proteomes of mouse myocardium during ischemia-reperfusion injury using mass spectrometry, we show that both Serpina3k protein expression and its lactylation at lysine 351 are increased upon reperfusion. Both Serpina3k and its human homolog, SERPINA3, are abundantly expressed in cardiac fibroblasts, but not in cardiomyocytes. Biochemically, lactylation of Serpina3k enhances protein stability. Using Serpina3k knockout mice and mice overexpressing its lactylation-deficient mutant, we find that Serpina3k protects from cardiac injury in a lysine 351 lactylation-dependent manner. Mechanistically, ischemia-reperfusion-stimulated fibroblasts secrete Serpina3k/SERPINA3, and protect cardiomyocytes from reperfusion-induced apoptosis in a paracrine fashion, partially through the activation of cardioprotective reperfusion injury salvage kinase and survivor activating factor enhancement pathways. Our results demonstrate the pivotal role of protein lactylation in cardiac ischemia-reperfusion injury, which may hold therapeutic value.

Suggested Citation

  • Le Wang & Dandan Li & Fang Yao & Shanshan Feng & Chao Tong & Rongjia Rao & Meiyan Zhong & Xianqiang Wang & Wei Feng & Zhan Hu & Bo Jin & Li Wang & Shengshou Hu & Bingying Zhou, 2025. "Serpina3k lactylation protects from cardiac ischemia reperfusion injury," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55589-w
    DOI: 10.1038/s41467-024-55589-w
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    References listed on IDEAS

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