Polyphyllin I inhibits glioblastoma progression by initiating ferroptosis via the Sirt1/Nrf2/HO-1/GPX4 signaling cascade

Abstract

Rationale

Glioblastoma is a fast-growing, invasive brain tumor with poor prognosis. Polyphyllin I, a saponin from Liliaceae plants, shows anti-tumor, anti-inflammatory effects, and induces ferroptosis, but its impact on glioblastoma and underlying mechanisms are not well understood.

Methods

Tumor malignancy was evaluated using assays such as scratch assays, CCK-8, clonogenic analyses, transwell experiments, along with EdU incorporation staining. Quantification for relevant molecules was performed using WB and RT-qPCR experiments. Ferroptosis in cells was quantified using JC-1, Boodipy, and TME assays. Lastly, the in vivo anti-tumor effects and mechanisms of Polyphyllin I were examined using a mouse xenograft model.

Results

This study reveals how PPI significantly inhibits GBM growth and spread while simultaneously improving the efficacy of chemotherapy drugs. In addition, the anti-tumor properties of PPI are linked to ferroptosis, and its effect is significantly diminished when ferroptosis is inhibited. Specifically, PPI binds directly to SIRT1, reducing its levels, which subsequently promotes oxidative cell death via the SIRT1/Nrf2/GPX4/HO-1 signaling pathway, thus suppressing glioblastoma. Furthermore, overexpression of SIRT1 can negate the therapeutic effects of PPI. The mouse xenograft model further supported the anti-tumor efficacy of PPI and provided deeper insights into its underlying mechanism.

Conclusions

Additionally, through regulating the SIRT1/Nrf2/GPX4/HO-1 axis, PPI induces iron-dependent cell death, contributing to its inhibition of glioblastoma. According to this research, PPI could serve as a superior treatment approach for GBM patients and holds promise for its combination with chemotherapy drugs in GBM treatment.