Polyphyllin I induces ferritinophagy dependent ferroptosis through EZH2 and promotes anti-tumor immunity

Biomed Pharmacother. 2025 Jun:187:118165. doi: 10.1016/j.biopha.2025.118165. Epub 2025 May 12.

Abstract

Background: Polyphyllin I (PPI), the primary active component extracted from the commonly utilized drug Paris polyphylla, in clinical applications, exhibits exceptional anti-tumor activity. Therefore, the objective of this study is to delve into its antitumor properties by promoting ferroptosis and enhancing anti-tumor immunity.

Results: Our result demonstrate that PPI effectively suppresses the proliferation of NSCLC cells and triggers their demise through the induction of ferroptosis. Furthermore, the degradation of iron via autophagy is pivotal in mediating PPI-induced ferroptosis in NSCLC. Notably, EZH2 emerges as a potential key target of PPI, and its overexpression can significantly attenuate the therapeutic efficacy of PPI. Lastly, these mechanistic insights and pathways were corroborated in animal model, and we preliminarily revealing a stimulatory role of PPI in bolstering anti-tumor immunity.

Conclusion: PPI triggers ferroptosis in NSCLC by downregulating EZH2, promoting NCOA4/Ferritin mediated ferritinophagy, and enhances anti-tumor immunity by promoting CD8 +T infiltration into tumor tissue.

Keywords: EZH2; Ferroptosis; Non-small cell lung cancer (NSCLC); Polyphyllin I.

MeSH terms

  • A549 Cells
  • Animals
  • Autophagy* / drug effects
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / immunology
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Diosgenin* / analogs & derivatives
  • Diosgenin* / pharmacology
  • Enhancer of Zeste Homolog 2 Protein* / metabolism
  • Ferritins* / metabolism
  • Ferroptosis* / drug effects
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / immunology
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Mice
  • Mice, Nude
  • Nuclear Receptor Coactivators / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Enhancer of Zeste Homolog 2 Protein
  • Ferritins
  • EZH2 protein, human
  • polyphyllin I
  • Diosgenin
  • Nuclear Receptor Coactivators