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Polyphyllin B induces ferroptosis in triple-negative breast cancer by inactivating NRF2

Ping Deng¹, Shouhai Zhu², Yuxuan Wu³

¹Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Frontiers in Pharmacology

|June 5, 2026

Abstract

Background:

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC) and lacks effective treatment options. Polyphyllin B (PB), a saponin extracted from Paris formosana Hayata, has shown potential in cancer therapy. However, its anti-TNBC effects and mechanisms are not well studied. This study investigated the effects and underlying mechanisms of PB in TNBC.

Methods:

CCK8 assay, Wound healing assay, Transwell migration experiments, and clonogenic assay were performed to assess the effects of PB in three TNBC cells lines. Iron level, lipid ROS, and MDA levels were assessed as ferroptosis markers. Mechanistic studies were conducted using molecular docking, Western blot, immunofluorescence, RT-qPCR, Nrf2 overexpression assays and establishment of a TNBC mouse model.

Results:

PB treatment resulted in significant cell death and inhibited the migration of TNBC cells. Accumulation of iron and MDA suggested that PB induces ferroptosis. In vitro and in vivo, PB downregulated the expression of nuclear factor E2-related factor 2 (NRF2) and sequestosome-1 (P62) and upregulated the expression of Kelch-like ECH-associated protein 1 (KEAP1). Furthermore, it modulated the expression of key ferroptosis regulators, including acyl-CoA synthetase long-chain family member 4 (ACSL4) and glutathione peroxidase 4 (GPX4). In a TNBC mouse model, PB suppressed tumor growth and increased malondialdehyde accumulation.

Conclusion:

PB inhibits cell proliferation and migration and induces ferroptosis in TNBC through the inactivation of NRF2. PB is a promising candidate for TNBC treatment that warrants further investigation.

Insights

Polyphyllin B (PB) effectively inhibits triple-negative breast cancer (TNBC) cell growth and migration. This natural compound induces ferroptosis by inactivating the NRF2 pathway, showing promise for TNBC treatment.

Area of Science:

Oncology
Pharmacology
Biochemistry

Background:

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic options.
Polyphyllin B (PB), a saponin from Paris formosana Hayata, exhibits potential anticancer properties.
The anti-TNBC effects and specific mechanisms of PB remain largely unexplored.

Purpose of the Study:

To investigate the efficacy of Polyphyllin B (PB) against triple-negative breast cancer (TNBC) cells.
To elucidate the underlying molecular mechanisms of PB's anti-TNBC activity.
To evaluate PB's therapeutic potential in a preclinical TNBC mouse model.

Main Methods:

Cell viability, migration, and colony formation assays were used to assess PB's effects on TNBC cell lines.
Ferroptosis markers, including iron levels and malondialdehyde (MDA), were analyzed.
Molecular mechanisms were explored via Western blot, RT-qPCR, immunofluorescence, molecular docking, and a TNBC mouse model, focusing on the NRF2 pathway.

Main Results:

PB significantly reduced TNBC cell proliferation and migration in vitro.
PB treatment led to iron accumulation and increased MDA levels, indicating ferroptosis induction.
In vitro and in vivo, PB suppressed tumor growth, downregulated NRF2 and P62, upregulated KEAP1, and modulated ferroptosis regulators ACSL4 and GPX4.

Conclusions:

Polyphyllin B (PB) inhibits TNBC cell proliferation and migration by inducing ferroptosis.
The mechanism involves the inactivation of the NRF2 signaling pathway.
PB demonstrates significant potential as a therapeutic agent for triple-negative breast cancer.

Read full analysis

Keywords:

Nrf2 breast cancer ferroptosis polyphyllin B triple negative breast cancer

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