Methylcobalamin protects against liver failure via engaging gasdermin E
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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54826-6 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Wanfeng Xu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-28bb8c8dcfd241a388ad541cbc4e4abf |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-28bb8c8dcfd241a388ad541cbc4e4abf2025-02-02T12:33:31ZengNature PortfolioNature Communications2041-17232025-01-0116111610.1038/s41467-024-54826-6Methylcobalamin protects against liver failure via engaging gasdermin EWanfeng Xu0Yun Wang1Shuang Cui2Qiuling Zheng3Yanghao Lin4Qingqing Cui5Yuxin Xie6Yuming Zeng7Chuan Zhang8Yujie Li9Xin Jin10Minna Qin11Huiyong Sun12Haiping Hao13Lijuan Cao14State Key Laboratory of Natural Medicines, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, China Pharmaceutical UniversityAbstract 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.https://doi.org/10.1038/s41467-024-54826-6 |
| spellingShingle | 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 Methylcobalamin protects against liver failure via engaging gasdermin E Nature Communications |
| title | Methylcobalamin protects against liver failure via engaging gasdermin E |
| title_full | Methylcobalamin protects against liver failure via engaging gasdermin E |
| title_fullStr | Methylcobalamin protects against liver failure via engaging gasdermin E |
| title_full_unstemmed | Methylcobalamin protects against liver failure via engaging gasdermin E |
| title_short | Methylcobalamin protects against liver failure via engaging gasdermin E |
| title_sort | methylcobalamin protects against liver failure via engaging gasdermin e |
| url | https://doi.org/10.1038/s41467-024-54826-6 |
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