1. Academic Validation
  2. Taraxerol induces ferroptosis in breast cancer by targeting Nrf2 transcriptional activity to promote MIB2-mediated GPX4 ubiquitination

Taraxerol induces ferroptosis in breast cancer by targeting Nrf2 transcriptional activity to promote MIB2-mediated GPX4 ubiquitination

  • Phytomedicine. 2025 Jun 25:145:157024. doi: 10.1016/j.phymed.2025.157024.
Pan Du 1 Anna Han 2 Jiajing Liu 1 Wenxuan Li 1 Xinyue Feng 1 Liyan Chen 3
Affiliations

Affiliations

  • 1 Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji 133000, PR China.
  • 2 Central Laboratory, Yanbian University Hospital, Yanji, Jilin 133000, PR China.
  • 3 Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji 133000, PR China. Electronic address: lychen@ybu.edu.cn.
Abstract

Background: Eradicating tumors through targeted Ferroptosis represents a novel approach to BC treatment. Taraxerol, a natural triterpenoid derived from dandelions, has shown anti-tumor effects. However, the Ferroptosis dependency of Taraxerol's Anticancer effects remains to be elucidated.

Purpose: This study aimed to explore the effects and molecular mechanism of action of taraxerol on Ferroptosis in BC.

Methods: The effects of Taraxerol on the proliferation, lipid peroxidation, iron accumulation, and glutathione (GSH) and malondialdehyde (MDA) levels in BC cells were investigated. Western blotting, qRT-PCR, Co-IP, and dual-luciferase reporter assays were used to detect Taraxerol-induced protein expression and regulation. Network pharmacology and molecular docking were employed to explore the regulation of ferroptosis-related signaling pathways and specific proteins by Taraxerol. The in vivo anti-tumor effect mediated by Taraxerol was explored using a xenograft tumor model.

Results: Taraxerol markedly inhibited BC cell proliferation both in vitro and in vivo, increasing lipid peroxidation and Fe2+ levels, and reducing GSH levels. Moreover, Taraxerol triggered Ferroptosis in BC cells by targeting Nrf2, which is involved in the PI3K/Akt/mTOR signaling pathway. It also promoted the ubiquitin-mediated degradation of GPX4 by regulating the interaction between Nrf2 and the E3 ubiquitin Ligase MIB2.

Conclusion: Our findings are the first to demonstrate that Taraxerol mediates Ferroptosis in BC via the Nrf2/MIB2/GPX4 axis, representing a potential therapeutic candidate for BC treatment.

Keywords

Breast cancer; Ferroptosis; Nrf2/MIB2/GPX4 axis; Taraxerol.

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