2. Academic Validation
  3. α-Hederin causes ferroptosis in triple-negative breast cancer through modulating IRF1 to suppress GPX4

α-Hederin causes ferroptosis in triple-negative breast cancer through modulating IRF1 to suppress GPX4

  • Phytomedicine. 2025 Jun:141:156611. doi: 10.1016/j.phymed.2025.156611.
Xue Wu 1,  Lingli Jin 2,  Disuo Ren 1,  Shaolong Huang 3,  Xinyu Meng 1,  Zhixuan Wu 4,  Chaoyue Lv 1,  Jiatong Ru 1,  Heyu Zhang 4,  Shuwei Zhang 1,  Jingxia Bao 1,  Ouchen Wang 5,  Erjie Xia 6
Affiliations

Affiliations

  • 1 Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Graduate school of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
  • 2 Tongji Hospital, School of Medicine, Tongji University, Shanghai 200092, China; Zhejiang Provincial People's Hospital, Zhejiang 325000, China.
  • 3 Graduate School of Xuzhou Medical University, Xuzhou, Jiangsu 221000, China.
  • 4 Graduate school of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
  • 5 Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: woc099@163.com.
  • 6 Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: xiaerjie@wmu.edu.cn.
PMID: 40153970 DOI: 10.1016/j.phymed.2025.156611
Abstract

Background: Breast Cancer ranks first in the global incidence rate of Cancer among women. Triple-negative breast Cancer (TNBC) is considered to be the most dangerous type because of the lack of specific therapeutic targets and rapid progression. The emergence of Ferroptosis provides a new therapeutic perspective for TNBC. α-Hederin is a triterpenoid saponin derived from the traditional Chinese medicine Ivy, which has been proven to have anti-cancer effects on various cancers, but its efficacy and mechanism of inducing Ferroptosis in TNBC remain to be further clarified.

Object: To investigate the effect and mechanism of α-Hederin induced Ferroptosis in TNBC.

Method: Cell viability was measured by CCK-8 assay, and cell proliferation and migration were evaluated by clone assay and scratch assay. The effect of α-Hederin on TNBC cell Apoptosis was assessed by flow cytometry. Transcriptomics searches for critical pathways. Intracellular and lipid Reactive Oxygen Species and Fe2+and Fe were detected by DCFH-DA probe, FerroOrange fluorescent probe and C11-BODIPY fluorescent probe, and the contents of malondialdehyde and reduced glutathione were detected by MDA and GSH kits. Erastin was used as a positive control for Ferroptosis and Ferrrostatin-1(Fer-1) as an inhibitor. The relationship between α-Hederin and GPX4, IRF was analyzed by western blot and si-RNA, and the association was further confirmed by molecular simulation docking, external SPR experiments, and luciferase experiments. Constructing xenograft mouse models and human derived Organoid models to evaluate the anti-TNBC efficacy of α-Hederin, and verifying the efficacy and Ferroptosis mechanism of the drug in vivo through HE staining and IHC.

Result: α-Hederin significantly inhibited the progression of TNBC. In vitro, α-Hederin decreased Cancer cell viability through Ferroptosis, increased glutathione degradation and MDA production, and promoted intracellular Fe2+ and ROS production, whereas Fer-1, an Ferroptosis inhibitor, reversed this effect. Mechanistically, molecular docking and SPR experiments showed binding of α-Hederin to the key regulator IRF1, and knockdown/overexpression of IRF1 significantly affected the expression of GPX4, a downstream target of the Ferroptosis pathway. In vivo, α-Hederin prevented tumor growth in xenograft and Organoid models via the IRF1/GPX4 axis.

Conclusion: We proved for the first time in this research that α-Hederin exerts anti-TNBC effects through a novel IRF1/GPX4 Ferroptosis pathway.

Keywords

Ferroptosis; GPX4; IRF1; Triple negative breast cancer; α-Hederin.

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