2. Academic Validation
  3. Targeting GRB2-Akt-SREBP1 signaling axis by saponins from Paris polyphylla Smith var. yunnanensis (Franch.) Hand.-Mazz to overcome cisplatin resistance in bladder cancer

Targeting GRB2-Akt-SREBP1 signaling axis by saponins from Paris polyphylla Smith var. yunnanensis (Franch.) Hand.-Mazz to overcome cisplatin resistance in bladder cancer

  • J Ethnopharmacol. 2025 Aug 27:354:120502. doi: 10.1016/j.jep.2025.120502.
Jue Liu 1,  Yue-Xuan Liu 1,  Yu-Song Song 1,  Chen-Kai Liu 1,  Fei-Xue Yu 1,  Gao Liu 2,  Tian-Rui Xu 3,  Jun Sang 4
Affiliations

Affiliations

  • 1 Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China.
  • 2 Yunnan University of Traditional Chinese Medicine, Kunming, 650500, China.
  • 3 Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China. Electronic address: tianruixu@kust.edu.cn.
  • 4 Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China. Electronic address: junsang@kust.edu.cn.
PMID: 40882789 DOI: 10.1016/j.jep.2025.120502
Abstract

Ethnopharmacological relevance: Paris polyphylla Smith var. yunnanensis (Franch.) Hand.-Mazz., known as "Chonglou" in traditional Chinese medicine, is clinically used in Cancer therapy, with saponins identified as the key antitumor constituents. However, the therapeutic potential and mechanisms of the total saponins from P. polyphylla var. yunnanensis (PPT) against bladder Cancer, particularly their ability to overcome chemoresistance, remain unexplored.

Aim of the study: This study aimed to investigate PPT's anti-bladder Cancer effects and mechanisms, with a focus on its potential to overcome cisplatin resistance.

Materials and methods: We established a UPLC-DAD method for saponin profiling and developed an eco-friendly extraction protocol using hydroxypropyl-β-cyclodextrin-assisted extraction combined with macroporous resin purification to prepare PPT. Anti-cancer efficacy was assessed in bladder Cancer cell lines, mouse/zebrafish xenograft models, and cisplatin-resistant models. Mechanistic investigations integrated network pharmacology, metabolomics, molecular docking, and experimental validations (siRNA silencing, western blotting, flow cytometry, molecular dynamics simulations, cellular thermal shift assay, and surface plasmon resonance).

Results: The hydroxypropyl-β-cyclodextrin-based extraction system enhanced PPT purity by 15-fold, with the purified fraction showing dose-dependent anti-bladder Cancer activity in vitro and in vivo. Mechanistically, PPT exerted anti-proliferative, pro-apoptotic, anti-lipogenic, and chemosensitizing effects by inhibiting the growth factor receptor binding protein 2 (GRB2)-mediated Akt-SREBP1 signaling axis. Notably, polyphyllin VII, a key constituent of PPT, was identified as a novel GRB2 inhibitor, potently suppressing bladder Cancer progression and overcoming cisplatin resistance.

Conclusion: This study demonstrates that targeting the GRB2-Akt-SREBP1 signaling axis is a promising strategy for bladder Cancer therapy, further establishing PPT as a multicomponent phytomedicine and PPVII as a novel GRB2 inhibitor with high translational potential.

Keywords

Drug resistance; GRB2 inhibitor; Green extraction; Natural products; Polyphyllin VII.

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