{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T08:06:14Z","timestamp":1789027574981,"version":"build-2803163510"},"reference-count":46,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Tumor drug resistance and metastasis are leading causes of cancer\u2011related mortality, both of which are tightly governed by multiple signaling pathways. The AKT\u2011GSK\u20113\u03b2 axis is a critical regulator of tumor progression, mediating drug resistance and epithelial\u2011mesenchymal transition (EMT) through its downstream targets. Aberrantly activated AKT\u2011GSK\u20113\u03b2 signaling modulates the expression and degradation of the drug efflux pump P\u2010gp, which expels chemotherapeutic agents, including paclitaxel (PTX), from cancer cells, resulting in chemotherapy failure and drug resistance. Moreover, hyperactivated AKT\u2011GSK\u20113\u03b2 signaling drives EMT, a key process closely linked to tumor metastasis and malignant progression. Dioscin (Dio), a natural steroidal saponin, exhibits significant anti\u2011tumor activity in multiple cancers. However, whether Dio reverses chemoresistance and inhibits tumor growth by targeting the AKT\u2011GSK\u20113\u03b2 pathway to promote P\u2010gp degradation and suppress EMT remains elusive, which is the central focus of this study. To explore whether Dio enhances the sensitivity of drug\u2010resistant cancer cells to PTX and inhibits cancer metastasis and the EMT process, as well as its potential mechanism(s). Paclitaxel\u2010resistant TE\u20101\/PTX and HeLa\/PTX cells were subjected to SRB, colony formation, Rh123 accumulation, wound\u2010healing, and Transwell assays to evaluate Dio's chemosensitizing, anti\u2010EMT, and anti\u2010metastatic effects. Network pharmacology, molecular docking, CETSA, and proteolysis assays verified a direct Dio\u2010AKT1 interaction. Western blotting, Co\u2010IP, and MG132 and MK2206 rescue experiments clarified AKT\/GSK3\u03b2\u2010dependent P\u2010gp ubiquitin\u2010proteasomal degradation and EMT suppression. HeLa\/PTX xenograft models were generated; H&amp;E staining and immunoblotting were used to assess tumor growth, biosafety, and intratumoral protein profiles for in vivo validation. Dio sensitized PTX\u2010resistant cells to paclitaxel, increased intracellular Rh123 accumulation, and inhibited cell migration and invasion. Mechanistically, Dio directly bound AKT1 to suppress AKT\/GSK3\u03b2 signaling, promoted ubiquitin\u2010proteasomal degradation of P\u2010gp, and reversed EMT by upregulating epithelial markers and repressing mesenchymal markers and EMT transcription factors. In vivo, Dio restrained xenograft tumor growth with negligible systemic toxicity, and intratumoral expression patterns of AKT\/GSK3\u03b2, P\u2010gp, and EMT\u2010related proteins mirrored in vitro findings. Dio has the potential to be a safe and effective agent for drug\u2010resistant cancer therapy.<\/jats:p>","DOI":"10.1002\/ddr.70366","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T15:04:58Z","timestamp":1786979098000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dioscin Reverses Drug Resistance via AKT\/GSK3\u03b2\u2010mediated P\u2010gp Degradation and EMT Inhibition"],"prefix":"10.1002","volume":"87","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7228-8186","authenticated-orcid":false,"given":"Keqi","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences Zhengzhou University Zhengzhou PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinzhu","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biotherapy and Cancer Center, West China Hospital Sichuan University Chengdu PR 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