2. Academic Validation
  3. Paris polyphylla Smith var. yunnanensis-derived saponins potentiate the antitumor activity of GPX4 inhibitors

Paris polyphylla Smith var. yunnanensis-derived saponins potentiate the antitumor activity of GPX4 inhibitors

  • J Ethnopharmacol. 2026 Feb 28:357:120890. doi: 10.1016/j.jep.2025.120890.
Yue-Xuan Liu 1,  Yu-Song Song 1,  Chen-Kai Liu 1,  Jue Liu 1,  Fei-Xue Yu 1,  Wu-Shuang Jiang 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: [email protected].
  • 4 Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China. Electronic address: [email protected].
PMID: 41232632 DOI: 10.1016/j.jep.2025.120890
Abstract

Ethnopharmacological relevance: Paris polyphylla Smith var. yunnanensis (Franch.) Hand.-Mazz. is a well-known medicinal herb valued in traditional medicine for its antitumor properties. Its primary bioactive constituents, saponins, exert anti-bladder Cancer effects by suppressing lipid metabolism. However, whether these saponins enhance the antitumor efficacy of Glutathione Peroxidase 4 (GPX4) inhibitors remains unexplored.

Aim of the study: This study aimed to investigate whether the total saponins of P. polyphylla var. yunnanensis (PPT) and its constituent polyphyllin VII (PPVII) inhibit the Akt-SREBP1 signaling axis and potentiate the antiproliferative activity of the GPX4 inhibitor JKE-1674 (JKE) across multiple Cancer types.

Materials and methods: The binding of PPVII to growth factor receptor binding protein 2 (GRB2) was assessed using site-directed mutagenesis and surface plasmon resonance. Antitumor activity was evaluated through in vitro assays (cell viability, Apoptosis, lipid ROS, Western blotting, colony formation) in various Cancer cell lines treated with PPT or PPVII, alone or in combination with JKE. Synergistic antitumor effects were confirmed in vivo using bladder Cancer xenograft models. To assess the clinical relevance of our targets, we analyzed data from public databases (UALCAN, TIMER3, The Human Protein Atlas) to correlate their expression levels with patient prognosis.

Results: Molecular interaction studies revealed that PPVII binds to GRB2 by targeting a critical clamp-like structure formed by residues ILE65, GLN157, TYR160, and PHE182. While the I65A mutation significantly reduced binding, the combined Q157A/Y160A/F182A mutation had a profoundly greater disruptive effect. Functionally, GRB2 inhibition suppressed the growth of chemoresistant bladder Cancer cells and enhanced gemcitabine sensitivity. Both PPT and PPVII suppressed the Akt-SREBP1 pathway and cell proliferation in bladder, breast, and liver Cancer models. Notably, PPT and PPVII dramatically potentiated the cytotoxicity of JKE. The JKE/PPVII combination synergistically induced oxidative stress-driven lipid peroxidation, endoplasmic reticulum stress, MAPK pathway activation, and Apoptosis in vitro, and exhibited potent antitumor efficacy in vivo. Bioinformatics confirmed GRB2 and GPX4 co-expression in liver Cancer, and the PPVII/JKE combination effectively suppressed LIHC cell proliferation.

Conclusion: This study validates GRB2 as a promising therapeutic target. P. polyphylla var. yunnanensis-derived saponins (PPT and PPVII) inhibit GRB2-mediated Akt-SREBP1 pathway activation in bladder, breast, and liver Cancer. Furthermore, combining PPVII with the GPX4 inhibitor JKE represents a novel, synergistic Cancer therapy strategy, acting through a mechanism that involves ROS-dependent activation of multiple cell death pathways.

Keywords

Drug resistance; GPX4 inhibitor; GRB2 inhibitor; Lipid metabolism; Polyphyllin VII.

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