ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1686526
Alkaloid-driven multi-target synergy of Tripterygium wilfordii polyglycosides overcomes cisplatin resistance in ovarian cancer by coordinated inhibition of PTPN11/EGFR/JAK signaling
Provisionally accepted- 1Shengli Clinical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
- 2Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China
- 3900th Hospital of the People's Liberation Army Joint Logistic Support Force, Fuzhou, China
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Objective: Tripterygium wilfordii polyglycoside (TWP) is a standardized extract from Tripterygium wilfordii Hook.f. and an oral prescription drug approved by the China Food and Drug Administration (now NMPA) for clinical use in inflammatory and autoimmune diseases. Leveraging its existing clinical approval, elucidating its anti-tumor mechanisms has high translational value for expanding its indications into oncology. This study aimed to clarify whether TWP can overcome cisplatin resistance in ovarian cancer and to explore a mechanism potentially centered on its alkaloid constituents through an integrated "prediction–validation" strategy. Methods: UPLC-QTOF- MS was used for chemical profiling. Network pharmacology predicted putative targets, validated by GEO transcriptomic datasets. Key alkaloid–target interactions were examined by molecular docking and 100-ns MD simulations. In vitro assays (CCK-8, Annexin V-FITC/PI, western blot) in cisplatin-resistant A2780/DDP cells confirmed phenotypic and mechanistic effects. Results: Thirty-eight constituents were identified, including 18 alkaloids. Five core targets (EGFR, JAK1, JAK2, PTPN11, SRD5A1) were pinpointed by network–clinical integration. Several alkaloids ranked among the top compounds by network degree, exhibited strong predicted binding affinities (ΔG ≤–7 kcal/mol), and formed stable complexes in molecular dynamics simulations. Functionally, TWP reduced viability, induced apoptosis, and de-phosphorylated EGFR, JAK1/2, and PTPN11, downregulated SRD5A1, and suppressed PI3K-AKT, JAK-STAT, and ERK-MAPK signaling. Conclusion: Our findings suggest that alkaloids in TWP may exert multi-target synergy to disrupt key survival pathways driving cisplatin resistance in ovarian cancer. These mechanistic insights not only rationalize its observed anti-tumor activity but also support its potential clinical repurposing from an approved anti-inflammatory drug to an oncology therapeutic.
Keywords: Tripterygium wilfordii polyglycoside, ovarian cancer, cisplatin resistance, Network Pharmacology, multi-target therapy, Alkaloids
Received: 15 Aug 2025; Accepted: 29 Sep 2025.
Copyright: © 2025 Ying, Lin and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Wang Ying, yingwang912@163.com
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