{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T09:23:48Z","timestamp":1780392228591,"version":"3.54.1"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T00:00:00Z","timestamp":1725408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Chem."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The increasing prevalence of recurrent spontaneous abortion (RSA) poses significant physical and psychological challenges for affected individuals. Quercetin, a natural plant flavonoid, shows promise in reducing miscarriage rates, yet its precise mechanism remains elusive. This study uses network pharmacology, molecular docking, and experimental validation to explore the molecular pathways through which quercetin mitigates RSA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Quercetin-related target genes were sourced from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and RSA target genes were retrieved from the Comparative Toxicogenomics Database (CTD), with overlapping targets identified using Venn diagrams. All genes were visualized using the STRING database, and core targets were selected with Cytoscape 3.7.3. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using the DAVID and Reactome online resources. Subsequently, HTR-8\/SVneo cells were stimulated with lipopolysaccharide (LPS) and treated with varying concentrations of quercetin (1, 5, and 10\u00a0\u03bcM), then subjected to CCK-8, wound healing, transwell, and annexin V-FITC\/PI apoptosis assays. Reverse-transcription quantitative PCR was used to determine the mRNA expression levels of IL-1\u03b2, TNF-\u03b1, and IL-6 in LPS-induced cells post-quercetin intervention, and western blotting was used to measure AKT1, MMP9, and caspase-3 protein levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 139 quercetin-associated target genes were identified from the TCMSP database, and 98 disease-associated target genes were obtained from the CTD, resulting in 25 shared target genes. Gene ontology enrichment highlighted the involvement of these targets in positive regulation of apoptosis, response to hypoxia, and intrinsic apoptotic signaling pathway in response to DNA damage. KEGG pathway analysis indicated enrichment in pathways related to interleukin-4 and interleukin-13 signaling, cytokine signaling in the immune system, and apoptosis. Molecular docking studies revealed robust binding of quercetin with MMP9, AKT1, IL-1\u03b2, TNF, and caspase-3. <jats:italic>In vitro<\/jats:italic> experiments demonstrated that quercetin enhanced LPS-induced cell activity, fostering proliferation, migration, and invasion, and reducing apoptosis. Moreover, quercetin reduced IL-1\u03b2, TNF-\u03b1, and IL-6 mRNA expression, increased AKT1 and MMP9 protein levels, and reduced caspase-3 expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Quercetin could mitigate the incidence of RSA by modulating inflammatory responses and apoptotic processes, through upregulation of AKT1 and MMP9, and downregulation of caspase-3, IL-1\u03b2, TNF-\u03b1, and IL-6. Quercetin opens up a new way of thinking about treating RSA.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fchem.2024.1407667","type":"journal-article","created":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T05:03:45Z","timestamp":1725426225000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["New molecular mechanisms of quercetin in improving recurrent spontaneous abortion based on in-depth network pharmacology and molecular docking"],"prefix":"10.3389","volume":"12","author":[{"given":"Dan","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuebing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruilin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxia","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongwei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,9,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1016\/j.kjms.2017.06.012","article-title":"Placental apoptosis in recurrent miscarriage","volume":"33","author":"Atia","year":"2017","journal-title":"Kaohsiung J. Med. Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e10956","DOI":"10.7759\/cureus.10956","article-title":"Role of low molecular weight heparin in the management of unexplained recurrent pregnancy loss: a review of literature","volume":"12","author":"Awolumate","year":"2020","journal-title":"Cureus"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.3390\/molecules29051000","article-title":"Quercetin, a flavonoid with great pharmacological capacity","volume":"29","author":"Carrillo-Martinez","year":"2024","journal-title":"Molecules"},{"key":"B4","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1016\/j.ydbio.2010.08.033","article-title":"Deletion of Akt1 causes heart defects and abnormal cardiomyocyte proliferation","volume":"347","author":"Chang","year":"2010","journal-title":"Dev. Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"101827","DOI":"10.1016\/j.tice.2022.101827","article-title":"Astragalus polysaccharides combined with Codonopsis pilosula polysaccharides modulates the physiological characteristics of trophoblasts via miR-92a-1-5p\/CCR7 axis","volume":"77","author":"Chen","year":"2022","journal-title":"Tissue Cell"},{"key":"B6","doi-asserted-by":"publisher","first-page":"118","DOI":"10.5603\/fhc.2012.0017","article-title":"Increased apoptotic activity on inflammatory human placentas in spontaneous abortions during the first and second trimester of gestation: a histochemical and immunohistochemical study","volume":"50","author":"Deftereou","year":"2012","journal-title":"Folia histochem. Cytobiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1097\/OGX.0000000000001033","article-title":"Recent advances in treatment of recurrent spontaneous abortion","volume":"77","author":"Deng","year":"2022","journal-title":"Obstet. Gynecol. Surv."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1468","DOI":"10.1177\/1933719119828051","article-title":"The possible involvement of miR-37la-5p regulating XIAP in the pathogenesis of recurrent pregnancy loss","volume":"26","author":"Du","year":"2019","journal-title":"Reprod. Sci. Thousand Oaks Calif."},{"key":"B9","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.bcp.2019.04.023","article-title":"The effects of flavonoids on human first trimester trophoblast spheroidal stem cell self-renewal, invasion and JNK\/p38 MAPK activation: understanding the cytoprotective effects of these phytonutrients against oxidative stress","volume":"164","author":"Ebegboni","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"68","DOI":"10.3724\/zdxbyxb-2022-0499","article-title":"Effects of quercetin on immune regulation at the maternal-fetal interface","volume":"52","author":"Fu","year":"2022","journal-title":"J. Zhejiang Univ. Med. Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1136\/postgradmedj-2014-132672","article-title":"Recurrent miscarriage: causes, evaluation and management","volume":"91","author":"Garrido-Gimenez","year":"2015","journal-title":"Postgrad. Med. J."},{"key":"B12","doi-asserted-by":"publisher","first-page":"e13510","DOI":"10.1111\/aji.13510","article-title":"Puerarin attenuates preeclampsia-induced trophoblast mobility loss and inflammation by modulating miR-181b-5p\/RBAK axis","volume":"87","author":"Guo","year":"2022","journal-title":"Am. J. Reprod. Immunol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/j.placenta.2022.06.015","article-title":"Puerarin protects against H2O2-induced apoptosis of HTR-8\/SVneo cells by regulating the miR-20a-5p\/VEGFA\/Akt axis","volume":"126","author":"He","year":"2022","journal-title":"Placenta"},{"key":"B14","doi-asserted-by":"publisher","first-page":"432","DOI":"10.31128\/AJGP-01-18-4459","article-title":"Recurrent pregnancy loss: a summary of international evidence-based guidelines and practice","volume":"47","author":"Hong Li","year":"2018","journal-title":"Aust. J. Gen. Pract."},{"key":"B15","doi-asserted-by":"publisher","first-page":"113564","DOI":"10.1016\/j.ecoenv.2022.113564","article-title":"Environmental BPDE induced human trophoblast cell apoptosis by up-regulating lnc-HZ01\/p53 positive feedback loop","volume":"237","author":"Huang","year":"2022","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1067661","DOI":"10.3389\/fimmu.2022.1067661","article-title":"Insights into the immunomodulatory regulation of matrix metalloproteinase at the maternal-fetal interface during early pregnancy and pregnancy-related diseases","volume":"13","author":"Jing","year":"2023","journal-title":"Front. Immunol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"562","DOI":"10.3390\/ijms11020562","article-title":"Hypericins as potential leads for new therapeutics","volume":"11","author":"Karioti","year":"2010","journal-title":"Int. J. Mol. Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.bbrc.2021.07.075","article-title":"Senolytic treatment modulates decidualization in human endometrial stromal cells","volume":"571","author":"Kusama","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B19","first-page":"3065","article-title":"Effects of shoutai pills on expression of Th1\/Th2 cytokine in maternal-fetal interface and pregnancy outcome","volume":"35","author":"Lai","year":"2010","journal-title":"Zhongguo Zhong Yao Za Zhi Zhongguo Zhongyao Zazhi China J. Chin. Mat. Medica"},{"key":"B20","doi-asserted-by":"publisher","first-page":"7495161","DOI":"10.1155\/2020\/7495161","article-title":"The efficacy of traditional Chinese medicine shoutai Pill combined with western medicine in the first trimester of pregnancy in women with unexplained recurrent spontaneous abortion: a systematic review and meta-analysis","volume":"2020","author":"Li","year":"","journal-title":"Biomed. Res. Int."},{"key":"B21","doi-asserted-by":"publisher","first-page":"CD010568","DOI":"10.1002\/14651858.CD010568.pub2","article-title":"Chinese herbal medicines for unexplained recurrent miscarriage","volume":"2016","author":"Li","year":"2016","journal-title":"Cochrane Database Syst. Rev."},{"key":"B22","doi-asserted-by":"publisher","first-page":"117890","DOI":"10.1016\/j.lfs.2020.117890","article-title":"Effects of resveratrol on autophagy and the expression of inflammasomes in a placental trophoblast oxidative stress model","volume":"256","author":"Li","year":"","journal-title":"Life Sci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"8251503","DOI":"10.1155\/2022\/8251503","article-title":"Shoutai wan improves embryo survival by regulating aerobic glycolysis of trophoblast cells in a mouse model of recurrent spontaneous abortion. Evid.-Based complement","volume":"2022","author":"Liang","year":"2022","journal-title":"Altern. Med. ECAM"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1007\/s43032-019-00034-3","article-title":"Quercetin prevents lipopolysaccharide-induced experimental preterm labor in mice and increases offspring survival rate","volume":"27","author":"Lin","year":"2020","journal-title":"Reprod. Sci. Thousand Oaks Calif."},{"key":"B25","doi-asserted-by":"publisher","first-page":"103283","DOI":"10.1016\/j.jri.2021.103283","article-title":"Interleukin-1 beta is significantly upregulated in the decidua of spontaneous and recurrent miscarriage placentas","volume":"144","author":"L\u00f6b","year":"2021","journal-title":"J. Reprod. Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"523","DOI":"10.3390\/nu14030523","article-title":"The role of macronutrients, micronutrients and flavonoid polyphenols in the prevention and treatment of osteoporosis","volume":"14","author":"Martiniakova","year":"2022","journal-title":"Nutrients"},{"key":"B27","doi-asserted-by":"publisher","first-page":"e12958","DOI":"10.1016\/j.heliyon.2023.e12958","article-title":"Hyperin promotes proliferation, migration, and invasion of HTR-8\/SVneo trophoblast cells via activation of JAK1\/STAT3 pathway in recurrent spontaneous abortions","volume":"9","author":"Mu","year":"2023","journal-title":"Heliyon"},{"key":"B28","doi-asserted-by":"publisher","first-page":"247054702210763","DOI":"10.1177\/24705470221076390","article-title":"The role of lipopolysaccharide-induced cell signalling in chronic inflammation","volume":"6","author":"Page","year":"2022","journal-title":"Chronic Stress"},{"key":"B29","doi-asserted-by":"publisher","first-page":"500","DOI":"10.3390\/ijms25010500","article-title":"Oleuropein stimulates migration of human trophoblast cells and expression of invasion-associated markers","volume":"25","author":"Pirkovi\u0107","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"804400","DOI":"10.3389\/fphar.2022.804400","article-title":"Psoralen promotes proliferation, migration, and invasion of human extravillous trophoblast derived HTR-8\/svneo cells in vitro by NF-\u03baB pathway","volume":"13","author":"Qi","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.fertnstert.2016.10.031","article-title":"Supplementation with progestogens in the first trimester of pregnancy to prevent miscarriage in women with unexplained recurrent miscarriage: a systematic review and meta-analysis of randomized, controlled trials","volume":"107","author":"Saccone","year":"2017","journal-title":"Fertil. Steril."},{"key":"B32","doi-asserted-by":"publisher","first-page":"e33173","DOI":"10.1097\/MD.0000000000033173","article-title":"Shoutai pills for threatened abortion: a protocol for systematic review and meta-analysis","volume":"102","author":"Song","year":"2023","journal-title":"Med. Baltim."},{"key":"B33","doi-asserted-by":"publisher","first-page":"103636","DOI":"10.1016\/j.jri.2022.103636","article-title":"Is there a place for Traditional Chinese Medicine (TCM) in the treatment of recurrent pregnancy loss?","volume":"152","author":"Sun","year":"2022","journal-title":"J. Reprod. Immunol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1242","DOI":"10.3390\/nu13041242","article-title":"Maternal quercetin consumption during pregnancy may help regulate total cholesterol\/HDL-cholesterol ratio without effect on cholesterol levels in male progeny consuming high-fat diet","volume":"13","author":"Takashima","year":"2021","journal-title":"Nutrients"},{"key":"B35","doi-asserted-by":"publisher","first-page":"4768","DOI":"10.3390\/jcm12144768","article-title":"The diagnostics and treatment of recurrent pregnancy loss","volume":"12","author":"Tomkiewicz","year":"2023","journal-title":"J. Clin. Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"4074","DOI":"10.3390\/jcm12124074","article-title":"Recurrent pregnancy loss etiology, risk factors, diagnosis, and management. Fresh look into a full box","volume":"12","author":"Turesheva","year":"2023","journal-title":"J. Clin. Med."},{"key":"B37","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1016\/j.tox.2011.10.017","article-title":"Maternal quercetin intake during pregnancy results in an adapted iron homeostasis at adulthood","volume":"290","author":"Vanhees","year":"2011","journal-title":"Toxicology"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1041138","DOI":"10.3389\/fimmu.2022.1041138","article-title":"Tumor immunomodulatory effects of polyphenols","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Immunol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"2025","DOI":"10.3389\/fimmu.2020.02025","article-title":"T helper (Th) cell profiles in pregnancy and recurrent pregnancy losses: Th1\/Th2\/Th9\/Th17\/Th22\/tfh cells","volume":"11","author":"Wang","year":"2020","journal-title":"Front. Immunol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"745262","DOI":"10.1155\/2011\/745262","article-title":"Quercetin and bornyl acetate regulate T\u2010lymphocyte subsets and INF\u2010\u03b3\/IL\u20104 ratio in utero in pregnant mice","volume":"2011","author":"Wang","year":"2011","journal-title":"Altern. Med. ECAM"},{"key":"B41","doi-asserted-by":"publisher","first-page":"847","DOI":"10.3892\/mmr.2021.12487","article-title":"Tumor necrosis factor inhibitors as therapeutic agents for recurrent spontaneous abortion (Review)","volume":"24","author":"Wu","year":"2021","journal-title":"Mol. Med. Rep."},{"key":"B42","doi-asserted-by":"publisher","first-page":"99","DOI":"10.3892\/mmr.2024.13223","article-title":"Protective effect of quercetin on lipopolysaccharide-induced miscarriage based on animal experiments and network pharmacology","volume":"29","author":"Wu","year":"2024","journal-title":"Mol. Med. Rep."},{"key":"B43","doi-asserted-by":"publisher","first-page":"132","DOI":"10.3390\/ijms24010132","article-title":"The update immune-regulatory role of pro- and anti-inflammatory cytokines in recurrent pregnancy losses","volume":"24","author":"Yang","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1038\/s41598-023-50712-1","article-title":"Quercetin stimulates trophoblast fusion via the mitochondrial function","volume":"14","author":"Yoshida","year":"2024","journal-title":"Sci. Rep."},{"key":"B45","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1007\/s12016-021-08907-9","article-title":"Role of inflammaging on the reproductive function and pregnancy","volume":"64","author":"Zavatta","year":"2023","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"113156","DOI":"10.1016\/j.jep.2020.113156","article-title":"Systematic biological and proteomics strategies to explore the regulation mechanism of Shoutai Wan on recurrent spontaneous Abortion\u2019s biological network","volume":"263","author":"Zeng","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1111\/aji.12447","article-title":"Association between serum TNF-\u03b1 levels and recurrent spontaneous miscarriage: a meta-analysis","volume":"75","author":"Zhang","year":"2016","journal-title":"Am. J. Reprod. Immunol. N. Y. N."},{"key":"B48","doi-asserted-by":"publisher","first-page":"e879","DOI":"10.1002\/iid3.879","article-title":"Inhibition of TMUB1 blocks apoptosis and NF\u2010\u03baB pathway\u2010mediated inflammation in recurrent spontaneous abortion","volume":"11","author":"Zhang","year":"2023","journal-title":"Inflamm. Dis."},{"key":"B49","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1142\/S0192415X02000120","article-title":"Anti-abortive effect of Radix scutellariae and rhizoma atractylodis in mice","volume":"30","author":"Zhong","year":"2002","journal-title":"Am. J. Chin. Med."},{"key":"B50","doi-asserted-by":"publisher","first-page":"775245","DOI":"10.3389\/fphar.2021.775245","article-title":"A potential mechanism of kidney-tonifying herbs treating unexplained recurrent spontaneous abortion: clinical evidence from the homogeneity of embryo implantation and tumor invasion","volume":"12","author":"Zhou","year":"","journal-title":"Front. Pharmacol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"965694","DOI":"10.3389\/fphar.2022.965694","article-title":"The effect of a traditional Chinese quadri-combination therapy and its component quercetin on recurrent spontaneous abortion: a clinical trial, network pharmacology and experiments-based study","volume":"13","author":"Zhou","year":"","journal-title":"Front. Pharmacol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.ijgo.2014.06.002","article-title":"\u201cNourishing the kidney\u201d and the treatment of recurrent pregnancy loss using traditional Chinese medicine","volume":"127","author":"Zhu","year":"2014","journal-title":"Int. J. Gynaecol. Obstet. Off. Organ Int. Fed. Gynaecol. Obstet."},{"key":"B53","doi-asserted-by":"publisher","first-page":"2702","DOI":"10.1111\/jcmm.14175","article-title":"Resveratrol promotes trophoblast invasion in pre\u2010eclampsia by inducing epithelial\u2010mesenchymal transition","volume":"23","author":"Zou","year":"2019","journal-title":"J. Cell. Mol. Med."}],"container-title":["Frontiers in Chemistry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2024.1407667\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T05:03:48Z","timestamp":1725426228000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2024.1407667\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,4]]},"references-count":53,"alternative-id":["10.3389\/fchem.2024.1407667"],"URL":"https:\/\/doi.org\/10.3389\/fchem.2024.1407667","relation":{},"ISSN":["2296-2646"],"issn-type":[{"value":"2296-2646","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,4]]},"article-number":"1407667"}}