Ge Qianxi, Wang Zhimin, Yu Jiaxiang, Feng Xiuzhi, Li Jiquan, Zhang Xiaoqing, Wang Shaohong, Wang Lie, Chen Yiran
Acupuncture and Moxibustion College, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China.
The First Clinical College, Liaoning University of Traditional Chinese Medicine, Shenyang, 100847, China.
Sci Rep. 2024 Dec 28;14(1):31224. doi: 10.1038/s41598-024-82486-5.
Ferroptosis is linked to various pathological conditions; however, the specific targets and mechanisms through which traditional Chinese medicine influences ischemic stroke (IS)-induced ferroptosis remain poorly understood. In this study, data from the Gene Expression Omnibus and disease target databases (OMIM, GeneCards, DisGeNet, TTD, and DrugBank) were integrated with ferroptosis-related gene datasets. To identify key molecular targets of Chuanxiong Rhizoma (CX), drug ingredient databases, including PubChem and TCMBank, were employed to map CX-related targets (CX-DEGs-FRG and CX-IS-FRG). Gene targets and relevant signaling pathways were analyzed using weighted gene co-expression network analysis, protein-protein interaction networks, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment. The least absolute shrinkage and selection operator regression and support vector machine methods were utilized to identify intersecting genes, and the predictive accuracy of core targets was evaluated through receiver operating characteristic curve analysis. Immune cell infiltration in the IS microenvironment was assessed using CIBERSORT, followed by molecular docking of CX's active components with key targets. The JAK-STAT3 pathway was identified as a critical regulatory mechanism, and five key targets (ALOX5, PTGS2, STAT3, G6PD, and HIF1A) emerged as central to the IS-induced ferroptosis. Elevated infiltration of CD8 + T cells and neutrophils was significantly correlated with IS. Notably, the active components mandenol and myricanone demonstrated strong binding affinities with these five targets, which validated the results from network-based analysis. In conclusion, the JAK-STAT3 pathway, through its regulation of ALOX5, PTGS2, STAT3, G6PD, and HIF1A, could play a crucial role in modulating ferroptosis and immune responses in IS. These findings suggest that CX could serve as a potential therapeutic approach for IS, targeting the regulation of IS-induced ferroptosis and the immune microenvironment.
铁死亡与多种病理状况相关；然而，中药影响缺血性中风（IS）诱导的铁死亡的具体靶点和机制仍知之甚少。在本研究中，将基因表达综合数据库和疾病靶点数据库（OMIM、GeneCards、DisGeNet、TTD和DrugBank）的数据与铁死亡相关基因数据集进行整合。为了鉴定川芎（CX）的关键分子靶点，利用包括PubChem和中药数据库在内的药物成分数据库来映射与CX相关的靶点（CX-DEGs-FRG和CX-IS-FRG）。使用加权基因共表达网络分析、蛋白质-蛋白质相互作用网络、基因本体论和京都基因与基因组百科全书通路富集分析基因靶点和相关信号通路。利用最小绝对收缩和选择算子回归以及支持向量机方法鉴定交集基因，并通过受试者工作特征曲线分析评估核心靶点的预测准确性。使用CIBERSORT评估IS微环境中的免疫细胞浸润，随后将CX的活性成分与关键靶点进行分子对接。JAK-STAT3通路被确定为关键调节机制，五个关键靶点（ALOX5、PTGS2、STAT3、G6PD和HIF1A）在IS诱导的铁死亡中起核心作用。CD8 + T细胞和中性粒细胞浸润增加与IS显著相关。值得注意的是，活性成分曼德诺醇和杨梅素与这五个靶点表现出强烈的结合亲和力，这验证了基于网络分析的结果。总之，JAK-STAT3通路通过调节ALOX5、PTGS2、STAT3、G6PD和HIF1A，可能在调节IS中的铁死亡和免疫反应中起关键作用。这些发现表明，CX可能作为IS的一种潜在治疗方法，靶向调节IS诱导的铁死亡和免疫微环境。
