Recently, Prof. Hai-Ping Hao's team published a research paper titled “Methylcobalamin protects against liver failure via engaging gasdermin E” online in Nature Communications. The research paper was published online in Nature Communications, which found that endogenous vitamin B12, methylcobalamin, is a specific inhibitor targeting GSDME, and can effectively intervene in GSDME-mediated liver failure. Researcher Lijuan Cao from State Key Laboratory of Multi-targeted Natural Medicines, Professor Haiping Hao and Distinguished Associate Researcher Huichong Sun from School of Pharmacy are the co-corresponding authors of this paper, Distinguished Researcher Wanfeng Xu, Dr. Eddie Wang, Distinguished Associate Researcher Shuang Cui, and Associate Professor Qiu-Ling Zheng from School of Pharmacy are the co-first authors, and China Pharmaceutical University is the first correspondent unit.
The focal death execution protein GSDME is ubiquitously expressed in a wide range of tissues/organs in the organism and plays a crucial role in infectious and non-infectious diseases, especially mediating severe organ damage caused by chemotherapeutic agents or enterovirus infection. Mechanistic studies suggest that caspase-3 or granzyme B mediates cholestatic, drug-induced and autoimmune liver injury through direct recognition and shearing of GSDME, but the crystal structure of GSDME remains unvalidated and few specific interventional drugs have been reported, and it remains unknown whether targeted inhibition of GSDME can intervene in liver failure mediated by it.
In this paper, research team constructed a high-throughput screening system by liposome leakage technology, and found that endogenous vitamin B12 methylcobalamin effectively interfered with the progression of GSDME-dependent diseases such as cholestatic, drug-induced, and autoimmune liver failure by inhibiting the upstream shear activation of caspase-3 and granzyme B, and then inhibiting the death of hepatocyte and macrophage by specifically binding to GSDME. The mechanism study revealed that methylcobalamin exposed its central cobalt element through base-off transitions to form a coordination bond with the Cys180 residue in the GSDME sequence, and the Cys180 site is essential for caspase-3 and GZmB to recognize and shear the GSDME, which ultimately blocked the activation of GSDME.
This study was supported by the National Natural Science Foundation of China, Jiangsu Zhuo Bo Program, Guangdong Provincial Medical Research Fund, Shenzhen Science and Technology Commission Basic Research Top Project and China Pharmaceutical University High-level Introduced Talents Research Project.
Link to the paper: https://www.nature.com/articles/s41467-024-54826-6
