自噬
水飞蓟宾
细胞生物学
基因敲除
车站3
生物
信号转导
ATG12
ATG5型
细胞凋亡
药理学
生物化学
作者
Wenbiao Li,Xinni Qu,Xiangping Kang,Haiyin Zhang,Zhang Xue-li,Haiyan Hu,Ling‐Ai Yao,Lina Zhang,Jing Zheng,Yuejuan Zheng,Jianghong Zhang,Yanwu Xu
标识
DOI:10.1016/j.ejphar.2022.175153
摘要
Growing evidence indicates that silibinin (SLB), a main component extracted from Chinese herb Silybum marianum, can effectively antagonize doxorubicin (DOX) induced myocardial injury (DIMI), but the specific molecular mechanism is still unelucidated. Herein, DOX induced human AC16 cardiomyocyte injury model and Network Pharmacology are used to predict and verify the potential mechanism. The analysis results of the core PPI network of SLB against DIMI show that JAK/STAT signaling pathway and autophagy are significantly enriched. Molecular docking results indicate that SLB has stronger binding ability to signaling key proteins IL6ST, JAK2 and STAT3 (affinity ≤ -7.0 kcal/mol). The detection results of pathway activation and autophagy level demonstrate that SLB significantly alleviates DOX induced IL6ST/JAK2/STAT3 signaling pathway inhibition and autophagy inhibition, reduces the death rate of cardiomyocytes. This protective effect of SLB is eliminated when key pathway proteins (IL6ST, JAK2, STAT3) are knocked down or autophagy is inhibited (3-MA or Beclin1 knockdown). These results suggest that the regulation of IL6ST/JAK2/STAT3 signaling pathway and autophagy may be important mechanism for SLB's protective effect on DOX injured cardiomyocytes. Further experimental results prove that knockdown of IL6ST, JAK2 and STAT3 eliminate the mitochondrial ROS scavenging effect and autophagy promoting effect of SLB. In sum, SLB can decrease the mitochondrial ROS and restore autophagy to antagonize DOX-induced cardiomyocyte injury by activating IL6ST/JAK2/STAT3 signaling pathway.
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