美国马萨诸塞大学医学院Katherine A. Fitzgerald研究团队取得最新进展。他们发现琥珀酸使胃泌素D（GSDMD）失活并阻止细胞焦亡。相关论文于2020年8月20日发表于《科学》。

他们通过将富马酸酯作为细胞焦亡的抑制剂来扩大这些观察结果。他们发现，递送至细胞或内源性富马酸的富马酸二甲酯（DMF）在临界半胱氨酸残基处与GSDMD反应形成S-（2-琥珀酰）-半胱氨酸。GSDMD琥珀酸阻止其与胱天蛋白酶的相互作用，限制其加工、寡聚和诱导细胞死亡的能力。在小鼠中，通过靶向GSDMD，DMF的给药可防止LPS休克并减轻家族性地中海热和实验性自身免疫性脑炎（EAE）。

总而言之，这些发现确定了GSDMD是富马酸盐的靶标，并揭示了基于富马酸盐的疗法（包括用于治疗多发性硬化症的DMF）的作用机制。

据介绍，活化的巨噬细胞经历代谢转换为有氧糖酵解，从而积累了改变免疫应答基因转录的Krebs循环中间体。

附：英文原文

Title: Succination inactivates gasdermin D and blocks pyroptosis

Author: Fiachra Humphries, Liraz Shmuel-Galia, Natalia Ketelut-Carneiro, Sheng Li, Bingwei Wang, Venkatesh V. Nemmara, Ruth Wilson, Zhaozhao Jiang, Farnaz Khalighinejad, Khaja Muneeruddin, Scott A. Shaffer, Ranjan Dutta, Carolina Ionete, Scott Pesiridis, Shuo Yang, Paul R. Thompson, Katherine A. Fitzgerald

Issue&Volume: 2020/08/20

Abstract: Abstract Activated macrophages undergo a metabolic switch to aerobic glycolysis accumulating Krebs cycle intermediates that alter transcription of immune response genes. Here we extend these observations by defining fumarate as an inhibitor of pyroptotic cell death. We found that dimethyl fumarate (DMF) delivered to cells or endogenous fumarate reacts with gasdermin D (GSDMD) at critical cysteine residues to form S-(2-succinyl)-cysteine. GSDMD succination prevents its interaction with caspases, limiting its processing, oligomerization, and capacity to induce cell death. In mice, the administration of DMF protects against LPS shock and alleviates familial Mediterranean fever and experimental autoimmune encephalitis (EAE) by targeting GSDMD. Collectively, these findings identify GSDMD as a target of fumarate and reveal a mechanism of action for fumarate-based therapeutics including DMF used to treat multiple sclerosis.

DOI: 10.1126/science.abb9818

Source: https://science.sciencemag.org/content/early/2020/08/19/science.abb9818