肝纤维化严重威胁人类健康，目前缺乏有效的治疗手段。肝纤维化的发病过程与肝细胞损伤，炎症反应失调，HSC增殖活化及细胞外基质分泌过度相关。有关细胞内能量感受器AMPK的最新研究进展显示其可促进细胞自噬、抑制炎症反应、抑制细胞增殖活化及改善细胞能量代谢，可能参与了肝脏纤维化进程，但目前尚无可直接激活AMPK且具有成药性的小分子化合物验证AMPK是否可真正成为抗肝纤维化药物靶标。依托早期研究基础，我们将利用已获得可直接激活AMPK的原创新型小分子C24和ZM582m，细胞水平评价化合物对HSC、肝细胞以及巨噬细胞的影响，结合基因操纵手段研究其作用是否与AMPK激活相关；在动物水平评估其对肝纤维化的治疗作用，结合组织特异性敲除小鼠确定AMPK依赖性。我们也将以直接激活剂为探针，深入探讨AMPK参与调控肝纤维化新机制，两者相互结合促进，为开发有效的抗肝纤维药物提供新的研究策略与先导化合物。

Liver fibrosis, for which there are few effective treatment strategies available, represents an enormous burden of human health. Recent researches indicate that the pathogenesis of liver fibrosis, is closely related to the excessive proliferation of myofibroblasts, the chronic inflammation and the abnormal energetic metabolic manners of the fibrosis tissues. More and more study indicates that cellular energy sensor AMPK, a inhibitor of inflammation and cell proliferation, as well as the core regulator of cell energetic metabolism, may involved in the pathogenesis of liver fibrosis. While the lack of the direct, drug-like activator made AMPK still an uncompleted proved target against liver fibrosis. Based on our previous study on autoinhibition regulatory mechanism existing in AMPK α subunit and novel screening method established against inactive AMPK α subunit, we found potent AMPK activator C24 and ZM582m. In this application, we aim to study the effect of C24 and ZM582m on HSC, macrophage and hepatocyte. Furthermore, the anti-liver fibrosis efficacy will also be evaluated. Meanwhile, specific gene silence and tissue specific knock-out mice models will be used to verify the dependent roles of AMPK in the therapeutic effect of its specific activators. We will also study the mechanism of anti-fibrosis by AMPK using these specific tools. We hope these studies can further prove the concept of AMPK as a novel anti-fibrosis drug target and provide first-in-class drug candidates.