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Methylcobalamin protects against liver failure via engaging gasdermin E

Author

Listed:
  • Wanfeng Xu

    (China Pharmaceutical University
    The Third Affiliated Hospital (The Affiliated Luohu Hospital) of Shenzhen University)

  • Yun Wang

    (China Pharmaceutical University)

  • Shuang Cui

    (China Pharmaceutical University)

  • Qiuling Zheng

    (China Pharmaceutical University
    China Pharmaceutical University)

  • Yanghao Lin

    (China Pharmaceutical University)

  • Qingqing Cui

    (China Pharmaceutical University)

  • Yuxin Xie

    (China Pharmaceutical University
    China Pharmaceutical University)

  • Yuming Zeng

    (China Pharmaceutical University)

  • Chuan Zhang

    (China Pharmaceutical University)

  • Yujie Li

    (China Pharmaceutical University)

  • Xin Jin

    (China Pharmaceutical University)

  • Minna Qin

    (China Pharmaceutical University)

  • Huiyong Sun

    (China Pharmaceutical University)

  • Haiping Hao

    (China Pharmaceutical University)

  • Lijuan Cao

    (China Pharmaceutical University)

Abstract

Gasdermin E (GSDME) is a pyroptotic cell death effector and a promising target for pyroptotic tissue injury. Here we perform high-throughput screening and demonstrate that methylcobalamin (MeCbl), an endogenous coenzyme form of vitamin B12, is a specific GSDME inhibitor and highly effective against cholestatic liver failure. MeCbl specifically blocks GSDME cleavage by directly binding with GSDME. In cholestasis-, cisplatin- or concanavalin A (Con A)-induced male mouse models, MeCbl significantly suppresses liver transaminase activities and inflammation, alleviates hepatocyte death, and reduces mortality of mice by blocking GSDME cleavage. The conserved Cys180 residue in GSDME is essential for caspase-3/GzmB recognition. MeCbl in base-off conformation coordinates to Cys180 to prevent caspase-3/GzmB-GSDME interactions and thereby GSDME-mediated pyroptosis. In summary, our study discovers MeCbl as a specific GSDME inhibitor that is promisingly to be developed as an effective drug against cholestatic liver failure, and other GSDME triggered sterile inflammation and/or organ failure.

Suggested Citation

  • Wanfeng Xu & Yun Wang & Shuang Cui & Qiuling Zheng & Yanghao Lin & Qingqing Cui & Yuxin Xie & Yuming Zeng & Chuan Zhang & Yujie Li & Xin Jin & Minna Qin & Huiyong Sun & Haiping Hao & Lijuan Cao, 2025. "Methylcobalamin protects against liver failure via engaging gasdermin E," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-54826-6
    DOI: 10.1038/s41467-024-54826-6
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    References listed on IDEAS

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