甘草次酸通过靶向IL-6/STAT3信号通路延缓骨髓造血干细胞衰老

The most significant change of intercellular communication in aging is "inflammation", in which IL-6 is the main inflammatory factor to accelerate aging . We screened 10000 kinds of natural products in combination with network pharmacology, and predicted that glycyrrhetinic acid (GA) could potentially target IL-6 through Surflex-Dock docking. We further verified the regulation of GA on IL-6/STAT3 in aging cells and old animals. The results showed that the number of galactosidase positive cells decreased after GA treatment. After GA administration, the hematopoiesis in spleen was relieved and the myeloid differentiation tendency of HSC was reversed. The preliminary mechanism study showed that GA could directly target IL-6 and specifically bind to IL-6 through BIAcore analysis, thus antagonizing the downstream JAK/STAT3 signaling pathway. We will further use IL-6R conditional knockout mice to verify the specificity of GA for IL-6 regulation. We will clarify the role and regulatory mechanism of GA on HSC aging.

衰老相关的最显著细胞间通讯改变就是“炎症”，而其中IL-6做为主要的炎症因子加速组织器官衰老。为此，我们以IL-6为靶标，结合网络药理学对一万种天然产物进行筛选，并通过Surflex-Dock对接预测发现，甘草次酸（Glycyrrhetinic acid，GA）潜在靶向IL-6。我们进一步在衰老细胞及年老动物水平验证GA对于IL-6/STAT3的调控。结果显示，加入GA培养后的衰老细胞中，半乳糖苷酶染色阳性细胞减少。给与GA后的衰老小鼠，其脾脏髓外造血得到缓解、骨髓造血干细胞的髓系分化倾向得到挽救。初步的机制研究发现，BIACore分子相互作用实验显示GA可以直接靶向IL-6并与IL-6特异性结合，WB实验验证GA拮抗下游JAK/STAT3信号通路。我们将进一步应用IL-6R造血系统特异性敲除小鼠验证GA对于IL-6调控的特异性，明确GA对骨髓造血干细胞衰老的作用及调控机制。

衰老是许多慢性疾病和功能损害的主要风险因素。炎症和衰老密切相关。甘草在中国和其他亚洲国家被广泛用于治疗各种炎症性疾病。我们提出，通过靶向特定的炎性细胞因子抑制衰老相关炎症可能有助于治疗衰老相关疾病。18β-甘草次酸（GA）是从甘草中提取的主要生物活性化合物。我们发现，在电离辐射（IR）诱导的人IMR-90成纤维细胞衰老中，GA降低了衰老相关的β-半乳糖苷酶（SA-β-Gal）活性。对自然衰老小鼠给予GA可使衰老的造血干细胞恢复活力，改善心脏功能，减轻脂肪组织炎症，改善能量代谢，减轻身体功能障碍。分子机制，我们通过表面等离子体共振分析发现GA直接与IL-6结合。分子模拟实验表明，GA抑制JAK2-STAT3信号传导。最后，我们研究了GA治疗的体内效应IL-6R敲除小鼠，我们发现IL-6R的敲除抑制了GA的作用。总之，我们的研究确定GA直接靶向IL-6，IL-6通过抑制JAK2/P53改善小鼠健康。我们的研究提供了相当大的临床有益治疗效果，可以减轻与年龄相关的功能障碍、严重的新冠肺炎肺炎和CAR-T治疗的炎症综合征。