目的 通过网络药理学和分子对接技术探究木糖-邻苯三酚结合物（XP）改善脓毒症相关急性肾损伤的潜在靶点，并采用动物实验验证其作用机制。方法 通过Swiss Target Prediction和PharmMapper数据库筛选XP的作用靶点，GeneCards、DrugBank、OMIM数据库检索脓毒症相关急性肾损伤的疾病靶点，将药物靶点与疾病靶点取交集获得潜在靶点。利用DAVID平台对潜在靶点进行基因本体（GO）、京都基因和基因组百科全书（KEGG）富集分析；采用Cytoscape 3.9.1软件绘制抗氧化剂XP改善脂多糖致脓毒症相关急性肾损伤的蛋白相互作用（PPI）网络图，选取degree值排名前10位的核心靶点和抗氧化剂XP作为受体蛋白和配体小分子，使用Schrödinger软件包进行受体和配体的分子对接，并开展核心靶点相关生物学通路的验证实验。结果 共筛选得到XP改善脂多糖致脓毒症相关急性肾损伤的作用靶点111个，其中核心靶点为白蛋白（ALB）、蛋白激酶B1（Akt1）、甘油醛-3-磷酸脱氢酶（GAPDH）、半胱氨酸蛋白水解酶3（CASP3）、酪氨酸激酶C（SRC）、雌激素受体1（ESR1）、90kDa热休克蛋白αA1（HSP90AA1）、V-Ha-Ras肉瘤病毒癌基因同源物（HRAS）、细胞周期素D1（CCND1）、丝裂原活化蛋白激酶1（MAPK1）。GO富集分析筛选出生物过程271条，细胞组成60条，分子功能100条；KEGG富集到生物学通路119条；分子对接结果显示XP与核心靶点均能够较好的结合。实验结果表明，XP可以显著改善脂多糖致脓毒症相关急性肾损伤的肾功能指标升高和肾组织病理损伤，其作用机制与上调肾脏组织中p-磷脂酰肌醇-3-激酶（PI3K）和p-Akt蛋白的表达相关。结论 XP可通过激活PI3K/Akt信号通路，减轻脓毒症相关急性肾损伤。

Objective To explore the potential targets of xylose-pyrogallol complexes (XP) in ameliorating sepsis associated acute kidney injury by network pharmacology and molecular docking methods, and to verify this mechanism in vivo. Methods The targets of XP were obtained by Swiss Target Prediction and PharMapper database, GeneCards, DrugBank and OMIM database searched the disease targets of sepsis associated acute kidney injury and the potential targets were obtained after the intersection of the drug targets and disease targets. DAVID platform was used for GO and KEGG enrichment analysis. Cytoscape 3.9.1 software was used to construct the PPI network of the intersection targets. Top ten core targets and XP were selected as receptors and small molecule ligand. Schrödinger software was used for molecular docking between receptors and ligand. Finally, the core targets and related biological pathway were confirmed by experiment. Results A total of 111 targets of XP were obtained for ameliorating sepsis associated acute kidney injury, and the core targets were ALB, Akt1, GAPDH, CASP3, SRC, ESR1, HSP90AA1, HRAS, CCND1, MAPK1. Items were screened by GO enrichment analysis, including 271 biological processes, 60 cellular components, and 100 molecular functions. KEGG was enriched to 119 gene pathways. Molecular docking results showed that XP had good affinity with the core targets. Animal experiment showed that XP could significantly alleviate the elevated levels of kidney function and the damage of kidney tissue in rats with sepsis associated acute kidney injury, and its mechanism was related to upregulate p-PI3K and p-Akt expression in kidney. Conclusion XP could alleviate sepsis associated acute kidney injury in rats by activating the PI3K/Akt signaling pathway.

R966

中国医学科学院医学与健康科技创新工程（2021-I2M-1-052）