AbstractCytokine storm (CS) emerges as an exacerbated inflammatory response triggered by various factors such as pathogens and excessive immunotherapy, posing a significant threat to life if left unchecked. Quercetin, a monomer found in traditional Chinese medicine, exhibits notable anti-inflammatory and antiviral properties.

摘要细胞因子风暴（CS）是由病原体和过度免疫治疗等各种因素引发的加剧的炎症反应，如果不加以控制，将对生命构成重大威胁。槲皮素是一种在中药中发现的单体，具有显着的抗炎和抗病毒特性。

This study endeavors to explore whether quercetin intervention could mitigate CS through a combination of network pharmacology analysis and experimental validation. First, common target genes and potential mechanisms affected by quercetin and CS were identified through network pharmacology, and molecular docking experiments confirmed quercetin and core targets.

本研究试图通过网络药理学分析和实验验证相结合，探讨槲皮素干预是否可以减轻CS。首先，通过网络药理学鉴定了槲皮素和CS影响的常见靶基因和潜在机制，分子对接实验证实了槲皮素和核心靶标。

Subsequently, in vitro experiments of Raw264.7 cells stimulated by lipopolysaccharide (LPS) showed that quercetin could effectively inhibit the overexpression of pro-inflammatory mediators and regulate the AKT1-FoxO1 signaling pathway. At the same time, quercetin can reduce ROS through the Keap1-Nrf2 signaling pathway.

随后，脂多糖（LPS）刺激的Raw264.7细胞的体外实验表明，槲皮素可以有效抑制促炎介质的过度表达并调节AKT1-FoxO1信号通路。同时，槲皮素可以通过Keap1-Nrf2信号通路减少ROS。

In addition, in vivo studies of C57BL/6 mice injected with LPS further confirmed quercetin's inhibitory effect on CS. In conclusion, this investigation elucidated novel target genes and signaling pathways implicated in the therapeutic effects of quercetin on CS. Moreover, it provided compelling evidence supporting the efficacy of quercetin in reversing LPS-induced CS, primarily through the regulation of the AKT1-FoxO1 and Keap1-Nrf2 signaling pathways..

此外，注射LPS的C57BL/6小鼠的体内研究进一步证实了槲皮素对CS的抑制作用。总之，这项研究阐明了与槲皮素对CS的治疗作用有关的新靶基因和信号通路。此外，它提供了令人信服的证据支持槲皮素逆转LPS诱导的CS的功效，主要是通过调节AKT1-FoxO1和Keap1-Nrf2信号通路。。

IntroductionCytokine storm (CS) is a systemic inflammatory syndrome with excessive hyperactivation of immune cells characterized by increased cytokine release, including interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and monocyte chemotactic protein 1 (MCP-1), which causes severe pathologic complications, such as sepsis, tissue damage, multiple organ failure, and ultimately, death1.

引言细胞因子风暴（CS）是一种全身性炎症综合征，免疫细胞过度活化，其特征是细胞因子释放增加，包括白细胞介素-6（IL-6），肿瘤坏死因子α（TNF-α）和单核细胞趋化蛋白1（MCP-1），导致严重的病理并发症，如败血症，组织损伤，多器官衰竭，最终导致死亡1。

CS might be stimulated by multiple factors such as pathogens, auto-inflammation, monogenic, or therapeutic intervention and the lungs are the main organ to be affected by CS2.Macrophages play a pivotal role in infection and inflammation as the principal innate immune cells, exerting crucial regulatory functions in pathological inflammation.

CS可能受到多种因素的刺激，如病原体，自身炎症，单基因或治疗干预，肺是受CS2影响的主要器官。巨噬细胞作为主要的先天免疫细胞在感染和炎症中起关键作用，在病理性炎症中发挥关键的调节功能。

Within the tissue microenvironment, they exhibit polarization into either the classically activated M1 phenotype, characterized by pro-inflammatory properties, or the alternatively activated M2 phenotype, which demonstrates anti-inflammatory characteristics. Dysregulation in macrophage phenotypes can result in unchecked inflammatory responses, thereby precipitating CS and subsequent tissue damage3.

在组织微环境中，它们表现出极化为经典激活的M1表型（以促炎特性为特征）或交替激活的M2表型（表现出抗炎特性）。巨噬细胞表型失调可导致未经检查的炎症反应，从而导致CS和随后的组织损伤3。

Considering the pivotal role of macrophages in CS progression, modulating macrophage overactivation emerges as a promising strategy for CS intervention.Quercetin, a flavonoid compound, possesses a spectrum of biological properties, including antioxidant, anti-inflammatory, antiviral, and neuroprotective effects4,5,6,7.

考虑到巨噬细胞在CS进展中的关键作用，调节巨噬细胞过度活化成为CS干预的有希望的策略。槲皮素是一种黄酮类化合物，具有一系列生物学特性，包括抗氧化，抗炎，抗病毒和神经保护作用4,5,6,7。

Research indicated that quercetin exerted its anti-inflammatory effects by targeting Syk/Src/IRAK-1 to inhibit LPS-induced macrophage activation, while also preventing LPS-induced oxidative stress and inflammation through pathways NOX2/ROS/NF-κB8,9. However, the specific targets and signaling pathways through which quercetin regulates CS r.

研究表明，槲皮素通过靶向Syk/Src/IRAK-1来抑制LPS诱导的巨噬细胞活化，同时通过NOX2/ROS/NF-κB8,9途径预防LPS诱导的氧化应激和炎症，从而发挥其抗炎作用。然而，槲皮素调节CS r的特定靶标和信号通路。

Data availability

数据可用性

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

本研究中使用和/或分析的数据集可根据合理要求从通讯作者处获得。

AbbreviationsBALF:

缩写BALF：

Bronchoalveolar lavage fluid

支气管肺泡灌洗液

BP:

BP公司：

Biological process

生物过程

CC:

抄送：

Cellular composition

细胞组成

COVID-19:

新型冠状病毒肺炎：

Coronavirus disease 2019

2019年冠状病毒病

CS:

CS公司：

Cytokine storm

细胞激素风暴

DEX:

Dexamethasone

地塞米松

DMSO:

二甲基亚砜：

Dimethyl sulphoxide

二甲基亚砜

FoxO:

福克斯：

Forkhead box proteins O

叉头盒蛋白O

GO:

转到：

Gene ontology

基因本体论

IL-6:

Interleukin-6

白细胞介素-6

iNOS:

Inducible nitric oxide synthase

诱导型一氧化氮合酶

Keap1:

标题1：

Kelch-like ECH-associated protein 1

Kelch样ECH相关蛋白1

KEGG:

桶：

Kyoto encyclopedia of genes and genomes

京都基因与基因组百科全书

LPS:

LPS：

Lipopolysaccharides

脂多糖

MCP-1:

MCP-1：

Monocyte chemotactic protein 1

单核细胞趋化蛋白1

MF:

MF公司：

Molecular function

分子功能

NO:

否：

Nitric oxide

一氧化氮

Nrf2:

Nrf2：

Nuclear factor erythroid 2-related factor

核因子红细胞2相关因子

PPI:

PPI：

Protein–protein interaction network

蛋白质-蛋白质相互作用网络

ROS:

活性氧：

Reactive oxygen species

活性氧类

TCM:

TCM：

Traditional Chinese medicine

中医学

TNF-α:

TNF-α：

Tumor necrosis factor α

肿瘤坏死因子α

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Download referencesAcknowledgementsThe authors thank Ping Lin, Jie Zhang and Qin Lin from the lab of experimental oncology for their great help in this study. The authors gratefully appreciate BioRender's modifications to the figures. The authors would like to thank all the reviewers who participated in the review and MJEditor (www.mjeditor.com) for their linguistic assistance during the preparation of this manuscript.FundingThis study was supported by the National Natural Science Foundation of China (NO.82260490), Sichuan Provincial Nature Science Foundation (2022NSFSC1379); Sichuan Science and Technology Programme (2022YFSY0054) and Technology Innovation Project of Chengdu Science and Technology (2020-YF05-00059-SN); Natural Science Foundation of Hainan Province (NO.821QN394); Science and technology research project on novel corona-virus pneumonia outbreak, West China Hospital, Sichuan University (HX-2019-nCoV-069).Author informationAuthor notesThese authors contributed equally: Jingyi Xu, Yue Li and Xi Yang.Authors and AffiliationsWest China School of Basic Medical Science and Forensic Medicine, Sichuan University, No.17, Section3, Renmin South Road, Chengdu, 610044, People’s Republic of ChinaJingyi Xu, Yue Li, Hong Li, Xi Xiao & Ying HuangDepartment of Medical Oncology, West China Hospital, Cancer Center, Sichuan University, No.37 Guoxue Lane, Chengdu, 610041, ChinaXi Yang, Jia You, Lingnan Zheng & Cheng YiDepartment of Integrated Traditional Chinese and Western Medicine, School of Medicine, Cancer Hospital, University of Electronic Science and Technology of China, Chengdu, 610041, ChinaHuawei LiDepartment of Radiation Oncology, Hainan Affiliated Hospital of Hainan Medical University (Hainan General Hospital), No.31, Longhua Road, Haikou, 570100, Chi.

下载参考文献致谢作者感谢实验肿瘤学实验室的林萍，张洁和秦琳在这项研究中的巨大帮助。作者非常感谢BioRender对数字的修改。作者要感谢所有参与评论的审稿人和MJEditor（www.MJEditor.com）在编写本手稿期间提供的语言帮助。资助本研究得到了国家自然科学基金（NO.82260490），四川省自然科学基金（2022NSFSC1379）的支持；四川省科技计划（2022YFSY0054）和成都市科技创新项目（2020-YF05-00059-SN）；海南省自然科学基金（NO.821QN394）；四川大学华西医院新型冠状病毒肺炎爆发科技研究项目（HX-2019-nCoV-069）。作者信息作者注意到这些作者做出了同样的贡献：徐静怡，李悦和杨曦。作者和单位四川大学中国基础医学与法医学院，中国人民南路3段17号，成都，610044，中华人民共和国徐静怡，李悦，李红，奚晓英，黄英四川大学肿瘤中心华西医院肿瘤内科，成都国学巷37号，610041，中国西安杨，贾优，岭南郑，程毅中国电子科技大学肿瘤医院医学院中西医结合科，成都，610041，中国华为海南医科大学附属医院放射肿瘤科综合医院），海口市龙华路31号，邮编570100。

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PubMed Google ScholarContributionsXu, Li, Yang, Li, Xiao, You, Li, Zheng, Li, Yi, and Huang contributed to this study. Xu, Li,ang contributed equally to this study. Yi, Li andHuang directed the design of this study, supervised its implementation and revised draft. Xu, Li, Yang, Li, Xiao participated in the specific experimental process, data analysis and paper writing.

PubMed谷歌学术贡献Xu，Li，Yang，Li，Xiao，You，Li，Zheng，Li，Yi和Huang为这项研究做出了贡献。Xu，Li，ang对这项研究做出了同样的贡献。易，李和黄指导了这项研究的设计，监督了它的实施和修订草案。徐，李，杨，李，肖参与了具体的实验过程，数据分析和论文写作。

You, Li, Zheng were involved in the charting of the paper. All authors have read and approved the final draft.Corresponding authorsCorrespondence to.

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Reprints and permissionsAbout this articleCite this articleXu, J., Li, Y., Yang, X. et al. Quercetin inhibited LPS-induced cytokine storm by interacting with the AKT1-FoxO1 and Keap1-Nrf2 signaling pathway in macrophages.

转载和许可本文引用本文Xu，J.，Li，Y.，Yang，X。等人。槲皮素通过与巨噬细胞中的AKT1-FoxO1和Keap1-Nrf2信号通路相互作用来抑制LPS诱导的细胞因子风暴。

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KeywordsCytokine stormMacrophagesNetwork pharmacologyQuercetinAKT1-FoxO1 pathwayKeap1-Nrf2 pathway

关键词细胞因子风暴巨噬细胞网络药理学槲皮素AKT1-FoxO1通路KEAP1-Nrf2通路

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