Table5_Mechanisms underlying the therapeutic effects of 4-octyl itaconate in treating sepsis based on network pharmacology and molecular docking.XLSX

Objective: Through network pharmacology and molecular docking technology, the hub genes, biological functions, and signaling pathways of 4-Octyl itaconate (4-OI) against sepsis were revealed.
Methods: Pathological targets of sepsis were screened using GeneCards and GEO databases. Similarly, the pharmacological targets of 4-OI were obtained through Swiss TargetPrediction (STP), Similarity ensemble approach (SEA), and TargetNet databases. Then, all the potential targets of 4-OI anti-sepsis were screened by the online platform Draw Venn diagram, and the hub genes were screened by Cytoscape software. The identified hub genes were analyzed by GO and KEGG enrichment analysis, protein interaction (PPI) network, and molecular and docking technology to verify the reliability of hub gene prediction, further confirming the target and mechanism of 4-OI in the treatment of sepsis.
Results: After the target screening of 4-OI and sepsis, 264 pharmacological targets, 1953 pathological targets, and 72 genes related to 4-OI anti-sepsis were obtained, and eight hub genes were screened, namely MMP9, MMP2, SIRT1, PPARA, PTPRC, NOS3, TLR2, and HSP90AA1. The enrichment analysis results indicated that 4-OI might be involved in regulating inflammatory imbalance, immunosuppression, and oxidative stress in developing sepsis. 4-OI protects multiple organ dysfunction in sepsis by acting on hub genes, and MMP9 is a reliable gene for the prognosis and diagnosis of sepsis. The molecular docking results showed that 4-OI binds well to the hub target of sepsis.
Conclusion: 4-OI plays an antiseptic role by regulating MMP9, MMP2, SIRT1, PPARA, PTPRC, NOS3, TLR2 and HSP90AA1. These Hub genes may provide new insights into follow-up research on the target of sepsis treatment.

研究目的：本研究借助网络药理学与分子对接技术，揭示4-辛基衣康酸（4-Octyl itaconate, 4-OI）抗脓毒症的核心基因（hub genes）、生物学功能及信号通路。
研究方法：采用GeneCards数据库及基因表达综合数据库（Gene Expression Omnibus, GEO）筛选脓毒症的病理靶点；同理，通过瑞士靶点预测平台（Swiss TargetPrediction, STP）、相似性集成方法（Similarity ensemble approach, SEA）及TargetNet数据库获取4-OI的药物作用靶点。随后借助在线韦恩图绘制平台Draw Venn diagram筛选得到4-OI抗脓毒症的全部潜在靶点，并通过Cytoscape软件筛选核心基因。对筛选得到的核心基因进行基因本体（Gene Ontology, GO）富集分析、京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）富集分析、蛋白质相互作用（Protein-Protein Interaction, PPI）网络分析及分子对接技术，以验证核心基因预测的可靠性，进一步明确4-OI治疗脓毒症的作用靶点与机制。
研究结果：经4-OI与脓毒症的靶点筛选后，共获得264个药物作用靶点、1953个病理靶点及72个4-OI抗脓毒症相关基因，并筛选得到8个核心基因，分别为基质金属蛋白酶9（Matrix Metalloproteinase 9, MMP9）、基质金属蛋白酶2（Matrix Metalloproteinase 2, MMP2）、沉默信息调节因子1（Silent Information Regulator 1, SIRT1）、过氧化物酶体增殖物激活受体α（Peroxisome Proliferator-Activated Receptor Alpha, PPARA）、蛋白酪氨酸磷酸酶受体C（Protein Tyrosine Phosphatase Receptor C, PTPRC）、一氧化氮合酶3（Nitric Oxide Synthase 3, NOS3）、Toll样受体2（Toll-like Receptor 2, TLR2）及热休克蛋白90α1（Heat Shock Protein 90 Alpha Family Class A Member 1, HSP90AA1）。富集分析结果显示，4-OI可能通过调控脓毒症发生发展过程中的炎症失衡、免疫抑制及氧化应激发挥作用；4-OI可通过作用于核心基因改善脓毒症患者的多器官功能障碍，其中MMP9是用于脓毒症预后与诊断的可靠基因。分子对接结果表明，4-OI可与脓毒症核心靶点实现良好结合。
研究结论：4-OI通过调控MMP9、MMP2、SIRT1、PPARA、PTPRC、NOS3、TLR2及HSP90AA1发挥抗脓毒症作用。上述核心基因可为脓毒症治疗靶点的后续研究提供新的思路。