Ischemic stroke is the second leading cause of death worldwide with limited medications and neuroinflammation was recognized as a critical player in the progression of stroke, but how to control the overactive neuroinflammation is still a long-standing challenge. Here, we designed a novel SIRT6 activator MDL-811 which remarkably inhibited inflammatory response in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and primary mouse microglia, which were abolished by silencing SIRT6. RNA-seq screening identified the forkhead box C1 (Foxc1) is a key gene evoked by MDL-811 stimulation and is required for the anti-inflammatory effects of MDL-811. We found MDL-811-activated SIRT6 directly interacted with enhancer of zeste homolog 2 (EZH2) and promoted deacetylation of EZH2 which could bind to the promoter of Foxc1 and upregulate its expression to modulate inflammation. Moreover, our data demonstrated that MDL-811 not only ameliorated sickness behaviors in neuroinflammatory mice induced by LPS, but also markedly reduced the brain injury in ischemic stroke mice in addition to promoting long-term functional recovery. Importantly, MDL-811 also exhibited strong anti-inflammatory effects in human monocytes isolated from ischemic stroke patients, underlying an interesting translational perspective. Taken together, MDL-811 could be an alternative therapeutic candidate for ischemic stroke and other brain disorders associated with neuroinflammation.

缺血性中风是世界范围内第二大死亡原因，用药有限，神经炎症被认为是中风进展中的关键因素，但是如何控制过度活跃的神经炎症仍然是一个长期的挑战。在这里，我们设计了一种新型的SIRT6激活剂MDL-811，该激活剂可显着抑制脂多糖（LPS）刺激的RAW264.7巨噬细胞和原代小鼠小胶质细胞的炎症反应，并通过沉默SIRT6使其消除。RNA-seq筛选确定了叉头盒C1（Foxc1）是MDL-811刺激诱发的关键基因，并且是MDL-811的抗炎作用所必需的。我们发现MDL-811激活的SIRT6与zeste同源物2（EZH2）的增强子直接相互作用，并促进EZH2的去乙酰化，而EZH2的脱乙酰化作用可能与EGFP的启动子结合Foxc1并上调其表达以调节炎症。此外，我们的数据表明，MDL-811不仅改善了LPS诱导的神经炎症小鼠的疾病行为，而且除了促进长期功能恢复外，还显着减少了缺血性中风小鼠的脑损伤。重要的是，MDL-811在从缺血性中风患者中分离出的人类单核细胞中也表现出强大的抗炎作用，这是一个有趣的翻译观点。两者合计，MDL-811可能是缺血性中风和其他与神经炎症相关的脑部疾病的替代治疗候选药物。