Methylcobalamin Protects Against Liver Failure Via Engaging Gasdermin E

Overview

Journal Nat Commun

Date 2025 Jan 31

PMID 39890804

Authors

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

Affiliations

Soon will be listed here.

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.

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