{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T05:54:59Z","timestamp":1790574899245,"version":"4.1.0"},"reference-count":30,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Food Science &amp; Nutrition"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Icariin, a prenylated flavonoid glycoside from Epimedium species, is a representative dietary polyphenol with antioxidant, anti\u2010inflammatory, and antitumor properties. Gastric cancer (GC) is a major non\u2010communicable chronic disease characterized by complex molecular alterations and dysregulated redox homeostasis, yet the molecular targets underlying the potential anti\u2010GC activity of icariin remain poorly defined. In this study, we integrated network pharmacology, bulk transcriptomic analysis (TCGA\u2010STAD; GSE15497, GSE84437, GSE84433, and GSE26253), and single\u2010cell RNA sequencing (GSE183904; 142,053 cells) to identify candidate icariin\u2010associated genes in GC. NOX4 expression, prognostic value, and tumor microenvironment characteristics were systematically evaluated. A NOX4\u2010positive endothelial cell (NOX4pos_Endo)\u2010associated molecular subtyping strategy and a LASSO\u2010Cox prognostic model were constructed and validated. Molecular docking and molecular dynamics simulation were performed to explore a potential interaction between icariin and NOX4, and AGS cells were used for in\u00a0vitro validation. Network pharmacology identified 24 overlapping icariin\u2013GC targets, among which NOX4 showed prominent prognostic relevance. NOX4 was upregulated in GC and associated with unfavorable prognosis across multiple cohorts. At the single\u2010cell level, NOX4 was predominantly expressed in an endothelial subpopulation characterized by angiogenesis\u2010, adhesion\u2010, and extracellular matrix remodeling\u2010related transcriptional features. Consensus clustering identified two molecular subtypes with distinct clinical outcomes and biological characteristics. A 5\u2010gene prognostic model comprising SPIRE1, PLCH1, KCNS3, SLC27A2, and GRP showed moderate predictive performance across independent cohorts. Molecular docking suggested a potential icariin\u2013NOX4 interaction involving Ser576 and Trp377, while molecular dynamics simulation supported the stability of the predicted binding pose. In AGS cells, icariin treatment was associated with reduced NOX4 expression and intracellular ROS levels. Overall, these findings identify NOX4 as a candidate icariin\u2010associated regulatory node in GC and suggest that NOX4\/ROS\u2010related signaling may contribute to the cellular response to icariin. Further experimental studies are required to determine whether NOX4 is a direct molecular target of icariin and to clarify its therapeutic relevance.<\/jats:p>","DOI":"10.1002\/fsn3.72390","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T04:56:43Z","timestamp":1790571403000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated Multi\u2010Omics and Single\u2010Cell Analyses Implicate\n                    <scp>NOX4<\/scp>\n                    as an Icariin\u2010Associated Oxidative Stress Regulatory Node in Gastric Cancer"],"prefix":"10.1002","volume":"14","author":[{"given":"Na","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Biochemistry, School of Preclinical Medicine Zunyi Medical University  Zunyi Guizhou China"},{"name":"Department of Pathology Zunyi Medical University  Zunyi Guizhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3637-0270","authenticated-orcid":false,"given":"Junyan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Zunyi Medical University  Zunyi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9737-7603","authenticated-orcid":false,"given":"Zuchao","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Preclinical Medicine Zunyi Medical University  Zunyi Guizhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijuan","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Preclinical Medicine Zunyi Medical University  Zunyi Guizhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guizhou Biomanufacturing Laboratory Affiliated Hospital of Zunyi Medical University  Zunyi China"},{"name":"Key Laboratory of Cell Engineering of Guizhou Province Affiliated Hospital of Zunyi Medical University  Zunyi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyi","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Preclinical Medicine Zunyi Medical University  Zunyi Guizhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4243-8834","authenticated-orcid":false,"given":"Chunming","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology Zunyi Medical University  Zunyi Guizhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5563-715X","authenticated-orcid":false,"given":"Bochen","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Urology, School of Medicine, Shanghai Tenth People's Hospital Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6632-2238","authenticated-orcid":false,"given":"Jiawei","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Preclinical Medicine Zunyi Medical University  Zunyi Guizhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,27]]},"reference":[{"issue":"11","key":"e_1_2_12_2_1","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1038\/nmeth.4463","article-title":"SCENIC: Single\u2010Cell Regulatory Network Inference and Clustering","volume":"14","author":"Aibar S.","year":"2017","journal-title":"Nature Methods"},{"issue":"1","key":"e_1_2_12_3_1","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1186\/s13059-016-1070-5","article-title":"Estimating the Population Abundance of 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(Basel)"},{"issue":"3","key":"e_1_2_12_7_1","doi-asserted-by":"crossref","first-page":"258","DOI":"10.3390\/antiox14030258","article-title":"Oxidative Stress and Redox Signaling in Gastric Cancer: From Mechanisms to Therapeutic Implications","volume":"14","author":"Chen Z.","year":"2025","journal-title":"Antioxidants"},{"issue":"10","key":"e_1_2_12_8_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41419-018-0953-7","article-title":"NADPH Oxidase 4 Regulates Anoikis Resistance of Gastric Cancer Cells Through the Generation of Reactive Oxygen Species and the Induction of EGFR","volume":"9","author":"Du S.","year":"2018","journal-title":"Cell Death & Disease"},{"key":"e_1_2_12_9_1","doi-asserted-by":"crossref","DOI":"10.3389\/fcell.2022.884412","article-title":"NADPH Oxidase 4: A Potential Therapeutic Target of Malignancy","volume":"10","author":"Gong S.","year":"2022","journal-title":"Frontiers in Cell and Developmental 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Y.","year":"2023","journal-title":"Frontiers in Pharmacology"},{"key":"e_1_2_12_15_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.canlet.2025.217731","article-title":"COL1A1\u2010Positive Endothelial Cells Promote Gastric Cancer Progression via the ANGPTL4\u2010SDC4 Axis Driven by Endothelial\u2010To\u2010Mesenchymal Transition","volume":"623","author":"Liu Q.","year":"2025","journal-title":"Cancer Letters"},{"issue":"8","key":"e_1_2_12_16_1","first-page":"7437","article-title":"Comprehensive Bioinformatics Analysis of NOX4 as a Biomarker for Pan\u2010Cancer Prognosis and Immune Infiltration","volume":"16","author":"Liu Y.","year":"2024","journal-title":"Aging (Albany NY)"},{"issue":"33","key":"e_1_2_12_17_1","doi-asserted-by":"crossref","first-page":"11877","DOI":"10.1074\/jbc.RA120.014723","article-title":"The NADPH Oxidase NOX4 Promotes the Directed Migration of Endothelial Cells by Stabilizing Vascular Endothelial Growth Factor Receptor 2 Protein","volume":"295","author":"Miyano K.","year":"2020","journal-title":"Journal of Biological Chemistry"},{"issue":"4","key":"e_1_2_12_18_1","doi-asserted-by":"crossref","DOI":"10.3390\/ph18040538","article-title":"Trends and Pitfalls in the Progress of Network Pharmacology Research on Natural Products","volume":"18","author":"Panossian A.","year":"2025","journal-title":"Pharmaceuticals"},{"issue":"6","key":"e_1_2_12_19_1","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1111\/jcmm.12263","article-title":"Transforming Growth Factor\u2010\u03b21 Requires NADPH Oxidase 4 for Angiogenesis in Vitro and in Vivo","volume":"18","author":"Peshavariya H. 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B.","year":"2013","journal-title":"Evidence\u2010Based Complementary and Alternative Medicine"},{"key":"e_1_2_12_31_1","doi-asserted-by":"crossref","DOI":"10.1155\/2020\/1646905","article-title":"Applications of Network Pharmacology in Traditional Chinese Medicine Research","volume":"2020","author":"Zhou Z.","year":"2020","journal-title":"Evidence\u2010Based Complementary and Alternative Medicine"}],"container-title":["Food Science &amp; Nutrition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/fsn3.72390","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/fsn3.72390","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/fsn3.72390","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T04:56:47Z","timestamp":1790571407000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/fsn3.72390"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,27]]},"references-count":30,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1002\/fsn3.72390"],"URL":"https:\/\/doi.org\/10.1002\/fsn3.72390","archive":["Portico"],"relation":{},"ISSN":["2048-7177","2048-7177"],"issn-type":[{"value":"2048-7177","type":"print"},{"value":"2048-7177","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,27]]},"assertion":[{"value":"2026-04-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e72390"}}