天然产物研究与开发 ›› 2026, Vol. 38 ›› Issue (5): 1074-1083.doi: 10.16333/j.1001-6880.2026.5.016 cstr: 32307.14.1001-6880.2026.5.016

• 数据研究 • 上一篇    下一篇

基于网络药理学与实验验证探讨白花丹素通过JAK-STAT信号通路抑制铁死亡减轻脓毒血症急性肾损伤

洪维灿1,2，王奕人1，夏士程1,2，张贻欣1,2，尹菲玚1,2，郭晓磊3，高  琴1,3*，叶红伟1,3*   

  1. 1蚌埠医科大学 心脑血管疾病基础与临床重点实验室；2蚌埠医科大学临床医学院；3蚌埠医科大学 生理学教研室，蚌埠 233000
  • 出版日期:2026-05-26 发布日期:2026-05-26
  • 基金资助:
    蚌埠医科大学“512人才计划”（by51201102）；大学生创新创业训练计划（S202410367011）

Mechanism of plumbagin in alleviating sepsis-associated acute kidney injury via inhibiting JAK-STAT signaling pathway mediated ferroptosis based on network pharmacology and experimental validation

HONG Wei-can1,2,WANG Yi-ren1,XIA Shi-cheng1,2,ZHANG Yi-xin1,2,YIN Fei-yang1,2,GUO Xiao-lei3,GAO Qin1,3*,YE Hong-wei1,3*   

  1. 1Key Laboratory of Basic and Clinical Cardiovascular Diseases,Bengbu Medical University;2College of Clinical Medicine,Bengbu Medical University;3Department of Physiology,Bengbu Medical University,Bengbu 233000,China
  • Online:2026-05-26 Published:2026-05-26

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摘要：

基于网络药理学与实验验证探讨白花丹素（plumbagin，PLB）是否通过JAK-STAT信号通路抑制铁死亡缓解脓毒血症急性肾损伤（sepsis-associated acute kidney injury，SA-AKI）。通过网络药理学和生物信息学方法获得PLB和SA-AKI的核心靶点群，使用分子对接技术对核心成分和核心靶点进行验证。通过盲肠结扎术（cecal ligation and puncture，CLP）诱导小鼠SA-AKI，并验证相关机制；HE染色观察小鼠肾脏组织病理学形态变化；检测小鼠血清中肌酐（creatinine，CRE）和尿素氮（blood urea nitrogen，BUN）水平，肾脏组织丙二醛（malondialdehyde，MDA）以及超氧化物歧化酶（superoxide dismutase，SOD）水平；DHE荧光探针检测肾脏活性氧（reactive oxygen species，ROS）水平；ELISA检测小鼠血清肿瘤坏死因子α（tumor necrosis factor-α，TNF-α）和白介素-1β（interleukin-1β，IL-1β）水平。Western blot检测肾脏组织Janus激酶2（Janus kinase 2，JAK2）、磷酸化JAK2（p-JAK2）、信号传导及转录激活蛋白3（signal transducer and activator of transcription 3，STAT3）、磷酸化STAT3（p-STAT3）和胱氨酸/谷氨酸反向转运体蛋白（cystine/glutamate antiporter xc- system，xCT）、谷胱甘肽过氧化物酶（glutathione peroxidase 4，GPX4）、铁死亡抑制蛋白1（ferroptosis suppressor protein 1，FSP1）的蛋白表达水平。网络药理学分析结果表明JAK2和STAT3为PLB的核心靶点，分子对接进一步验证PLB可与JAK2和STAT3结合。与CLP组相比，HE染色显示不同剂量PLB改善了SA-AKI中肾脏发生的病理变化；不同剂量PLB处理后，降低了肾功能指标（CRE、BUN）、炎症因子（TNF-α、IL-1β）和氧化应激水平（MDA水平下降，SOD水平升高，ROS水平下降），并下调了p-JAK2、p-STAT3蛋白表达，上调了铁死亡相关蛋白xCT、GPX4和FSP1的表达。综上，PLB可能通过抑制JAK-STAT通路、抑制铁死亡缓解SA-AKI。

关键词: 网络药理学, 白花丹素, 脓毒血症急性肾损伤, 铁死亡, JAK-STAT通路

Abstract:

This study aims to investigate the mechanism of plumbagin (PLB) on alleviating sepsis-associated acute kidney injury (SA-AKI) via inhibiting JAK-STAT signaling pathway mediated ferroptosis based on network pharmacology and experimental validation. The target groups of PLB and SA-AKI were screened by network pharmacology and bioinformatics methods, and molecular docking was employed to validate the interactions between the core component and the core targets. The mouse SA-AKI model was induced by cecal ligation and puncture (CLP) to validate the related mechanisms. Renal tissue morphological changes were observed via HE staining. Serum levels of creatinine (CRE) and urea nitrogen (BUN), as well as the kidney tissue levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were measured. Renal reactive oxygen species (ROS) levels were detected using DHE fluorescent probe. Serum levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured by ELISA Method. The protein expression levels of Janus kinase 2 (JAK2), phosphorylated JAK2 (p-JAK2), signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3 (p-STAT3), and cystine/glutamate antiporter xc- system (xCT), glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1) in kidney tissue were detected by Western blot. Network pharmacology analysis identified JAK2 and STAT3 as the core targets, molecular docking further verified that PLB could bind to both JAK2 and STAT3. When compared with CLP group, in the different doses of PLB groups, HE staining showed that the different doses of PLB ameliorated the pathological changes of kidney tissue. PLB treatment reduced the levels of renal function indicators (CRE, BUN), inflammatory factors (TNF-α, IL-1β), and oxidative stress levels (decreased MDA, increased SOD, decreased ROS). It also downregulated the protein expression of p-STAT3 and p-JAK2, while upregulating the expression of ferroptosis-related proteins xCT, GPX4, and FSP1. In conclusion, PLB may alleviate SA-AKI by inhibiting JAK-STAT signaling pathway mediated ferroptosis in mice model.

Key words:

network pharmacology, plumbagin; sepsis-induced acute kidney injury, ferroptosis, JAK-STAT signaling pathway

中图分类号:  R966

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