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

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.