{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T14:53:53Z","timestamp":1782312833299,"version":"3.54.5"},"reference-count":39,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82374095"],"award-info":[{"award-number":["82374095"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Phytotherapy Research"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remains a significant obstacle in treating non\u2010small cell lung cancer (NSCLC). There is an urgent need for novel therapeutic approaches to overcome such resistance. This study aimed to investigate the potential of\n                    <jats:italic>Magnoliae flos<\/jats:italic>\n                    (MF) to reverse EGFR\u2013TKI resistance and to elucidate its underlying molecular mechanisms. Network pharmacology was employed to predict the anti\u2010NSCLC potential and molecular targets of MF. Predictions were validated through in\u00a0vitro and in\u00a0vivo experiments, including cell viability assays, flow cytometry for apoptosis and cell\u2010cycle analysis, wound\u2010healing assays, hierarchical extraction, high\u2010performance liquid chromatography\u2010mass spectrometry (HPLC\u2010MS), Western blotting, small\u2010molecule inhibitor screening, and patient\u2010derived xenograft (PDX) models. Bioinformatics analyses were conducted to identify signaling pathways associated with EGFR\u2010TKI resistance. Bioinformatics analysis suggested that MF modulates signaling pathways implicated in EGFR\u2010TKI resistance. In the PDX model of EGFR\u2010TKI\u2010resistant NSCLC, the chloroform layer extract of MF (Ext. C) significantly suppressed tumor growth. Ext. C inhibited the EGFR\/PI3K\/AKT pathway, reduced EGFR protein expression, induced apoptosis, arrested the cell cycle, and impaired cell migration. HPLC\u2010MS analysis identified magnolin (Mag), fargesin (Far), and kobusin (Kob) as bioactive compounds. Functional assays demonstrated these monomers exerted a synergistic anti\u2010tumor effect, with Mag showing the greatest potency. Small\u2010molecule inhibitor screening further revealed that Mag shortened the half\u2010life of EGFR by promoting its ubiquitination and degradation. MF and its active constituents exhibit potent anti\u2010tumor activity against EGFR\u2010TKI\u2010resistant NSCLC by promoting EGFR ubiquitination and downregulation of the EGFR\/PI3K\/AKT pathway. These findings suggest MF as a promising therapeutic candidate for overcoming EGFR\u2010TKI resistance and provide a basis for further preclinical development.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70311","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T13:30:42Z","timestamp":1775655042000},"page":"3613-3627","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>\n                      <i>Magnoliae flos<\/i>\n                    <\/scp>\n                    Overcomes\n                    <scp>EGFR<\/scp>\n                    \u2010\n                    <scp>TKI<\/scp>\n                    Resistance in\n                    <scp>NSCLC<\/scp>\n                    by Enhancing\n                    <scp>EGFR<\/scp>\n                    Ubiquitination"],"prefix":"10.1002","volume":"40","author":[{"given":"Qing","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Medical Oncology The First Affiliated Hospital of Xi'an Jiaotong University  China"},{"name":"School of Pharmacy, Health Science Center, Xi'an Jiaotong University  China"},{"name":"State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering  China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Su","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Health Science Center, Xi'an Jiaotong University  China"},{"name":"State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering  China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3875-0135","authenticated-orcid":false,"given":"Man","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Health Science Center, Xi'an Jiaotong University  China"},{"name":"State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering  China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianfeng","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Health Science Center, Xi'an Jiaotong University  China"},{"name":"State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering  China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology The First Affiliated Hospital of Xi'an Jiaotong University  China"},{"name":"School of Pharmacy, Health Science Center, Xi'an Jiaotong University  China"},{"name":"State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering  China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Health Science Center, Xi'an Jiaotong University  China"},{"name":"State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering  China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayan","family":"Ren","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Health Science Center, Xi'an Jiaotong University  China"},{"name":"State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering  China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuhong","family":"Peng","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Health Science Center, Xi'an Jiaotong University  China"},{"name":"State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering  China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Health Science Center, Xi'an Jiaotong University  China"},{"name":"State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering  China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanmin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology The First Affiliated Hospital of Xi'an Jiaotong University  China"},{"name":"School of Pharmacy, Health Science Center, Xi'an Jiaotong University  China"},{"name":"State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering  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W.2014.\u201cStudy on the Chemical Components and Pharmacological Activity of Magnolia Denudate.\u201dDesr. Master's Thesis South\u2010Central Minzu University."},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2018.06.030"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/1878\u20100261.13500"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2023.154858"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3002006"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2025.1617788"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm759"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1163485"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.19238"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.01626"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.891802"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2010.97"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43018\u2010024\u201000781\u20106"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010018\u20100777\u20101"},{"key":"e_1_2_12_37_1","unstructured":"Yang G.2017.\u201cQuality Control and Pharmacokinetic Study ofM. biondiiBased on Chemical Characterization and Improved Pattern Recognition Approach.\u201dDoctoral diss. Second Military Medical University."},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045\u2010022\u201001248\u2010w"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010018\u20100660\u20104"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27123697"}],"container-title":["Phytotherapy Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ptr.70311","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ptr.70311","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ptr.70311","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T14:34:11Z","timestamp":1782311651000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ptr.70311"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,8]]},"references-count":39,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1002\/ptr.70311"],"URL":"https:\/\/doi.org\/10.1002\/ptr.70311","archive":["Portico"],"relation":{},"ISSN":["0951-418X","1099-1573"],"issn-type":[{"value":"0951-418X","type":"print"},{"value":"1099-1573","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,8]]},"assertion":[{"value":"2025-04-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}