Serpina3k lactylation protects from cardiac ischemia reperfusion injury

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 () and Bingying Zhou ()
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Le Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Dandan Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Fang Yao: Chinese Academy of Medical Sciences and Peking Union Medical College
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
Shengshou Hu: Chinese Academy of Medical Sciences and Peking Union Medical College
Bingying Zhou: Chinese Academy of Medical Sciences and Peking Union Medical College

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-55589-w

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