{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T05:00:46Z","timestamp":1775624446223,"version":"3.50.1"},"reference-count":51,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"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":["Phytotherapy Research"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Overexpression of P\u2010glycoprotein (P\u2010gp) in non\u2010small cell lung cancer (NSCLC) cells is one of the primary causes of multidrug resistance (MDR), but the molecular mechanism remains obscure. Murine double minute 2 (MDM2) has been implicated in drug resistance across multiple cancer types. In this study, we investigated the potential mechanism of MDM2 on P\u2010gp\u2010mediated MDR of NSCLC and explored the potential therapeutic effects of 20(R)\u2010ginsenoside Rg3 (Rg3). Western blot, RT\u2010PCR, and immunohistochemistry (IHC) were applied to analyze the expression of critical signaling markers. The drug accumulation in resistant cells was measured using flow cytometry and confocal microscopy. Bioinformatics analysis, co\u2010immunoprecipitation (co\u2010IP), and immunofluorescence were conducted to confirm the protein\u2013protein interactions. MTT, colony formation, EdU, and in\u00a0vivo cell line derived xenograft (CDX) models were applied to validate therapeutic agents and molecular mechanisms. We demonstrated that MDM2 acted as a positive upstream regulator of P\u2010gp, and the inhibition of MDM2 by Rg3 increased the sensitivity of resistant cells to taxol treatment both in\u00a0vivo and in\u00a0vitro. Mechanistically, we uncovered that MDM2 bound to I\u03baB\u2010\u03b1, facilitating its ubiquitination degradation, which subsequently promoted NF\u2010\u03baB pathway activation to drive the high expression of P\u2010gp. Notably, Rg3 blocked this process by inhibiting MDM2. Moreover, interference with the NF\u2010\u03baB pathway reversed the regulation of P\u2010gp expression by MDM2. Our findings elucidate the molecular mechanisms of Rg3 in the treatment of P\u2010gp\u2010mediated MDR in NSCLC. This study also provides a new strategy to overcome P\u2010gp\u2010mediated MDR by inhibiting the MDM2\u2010I\u03baB\u2010\u03b1 signaling axis.<\/jats:p>","DOI":"10.1002\/ptr.70242","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T06:00:32Z","timestamp":1770098432000},"page":"1935-1950","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["20(R)\u2010Ginsenoside Rg3 Suppresses P\u2010Glycoprotein\u2010Mediated Multidrug Resistance in\n                    <scp>A549<\/scp>\n                    \/Taxol Cells by Targeting\n                    <scp>MDM2<\/scp>\n                    \u2010\n                    <scp>I\u03baB<\/scp>\n                    \u2010\u03b1 Signaling Axis"],"prefix":"10.1002","volume":"40","author":[{"given":"Yuying","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Pharmacology Shenyang Pharmaceutical University  Shenyang 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