Xu Wanfeng, Wang Yun, Cui Shuang, Zheng Qiuling, Lin Yanghao, Cui Qingqing, Xie Yuxin, Zeng Yuming, Zhang Chuan, Li Yujie, Jin Xin, Qin Minna, Sun Huiyong, Hao Haiping, Cao Lijuan
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, P. R. China.
Department of Pharmacy, The Third Affiliated Hospital (The Affiliated Luohu Hospital) of Shenzhen University, Shenzhen, 518001, P. R. China.
Nat Commun. 2025 Jan 31;16(1):1233. doi: 10.1038/s41467-024-54826-6.
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.
Gasdermin E（GSDME）是一种焦亡细胞死亡效应因子，也是焦亡组织损伤的一个有前景的靶点。在此，我们进行了高通量筛选，并证明维生素B12的内源性辅酶形式甲钴胺（MeCbl）是一种特异性GSDME抑制剂，对胆汁淤积性肝衰竭非常有效。MeCbl通过直接与GSDME结合，特异性地阻断GSDME的切割。在胆汁淤积、顺铂或刀豆蛋白A（Con A）诱导的雄性小鼠模型中，MeCbl通过阻断GSDME的切割，显著抑制肝转氨酶活性和炎症，减轻肝细胞死亡，并降低小鼠死亡率。GSDME中保守的半胱氨酸180残基对于caspase-3/GzmB识别至关重要。处于碱基脱离构象的MeCbl与半胱氨酸180配位，以防止caspase-3/GzmB-GSDME相互作用，从而防止GSDME介导的焦亡。总之，我们的研究发现MeCbl是一种特异性GSDME抑制剂，有望被开发成为一种有效的药物，用于治疗胆汁淤积性肝衰竭以及其他由GSDME引发的无菌性炎症和/或器官衰竭。
