Magnolol triggers ferroptosis in triple-negative breast cancer through modulation of the ETS2/SLC7A11/GPX4 signaling axis.

Authors

Jing Zhu, Ke Zhong, Yan Zhuang, Ao Cai, Yu-Han Zhou, Jie Yuan, Feng Ding, Long Zhao, Yu-Xin Zhang, Bo-Han Li, Cheng-Zhu Wu, Hong-Mei Li

Published in

Frontiers in pharmacology. Volume 17. Pages 1876648. Epub Jul 31, 2026.

Abstract

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation (LPO), represents a promising therapeutic strategy. Magnolia officinalis, a traditional herb for resolving dampness and phlegm, is known to modulate cellular metabolism. While magnolol (MAG), a bioactive neolignan from M. officinalis, shows anti-TNBC activity, its role in inducing ferroptosis remains unexplored.
Anti-TNBC effects of MAG were assessed in MDA-MB-231 and 4T1 cells via viability, apoptosis, and ferroptosis assays (intracellular Fe²⁺, LPO, GSH). Target identification employed network pharmacology, RNA-seq, surface plasmon resonance, and pull-down assays. Mechanisms were validated using siRNA/overexpression, Co-IP, and immunofluorescence. In vivo efficacy was evaluated in xenograft models.
MAG inhibited proliferation and induced apoptosis and ferroptosis in TNBC cells, evidenced by elevated Fe²⁺ and lipid peroxidation, depleted GSH, downregulated SLC7A11/GPX4, and mitochondrial shrinkage effects reversed by ferroptosis inhibitors. MAG directly bound and suppressed transcription factor ETS2. ETS2 knockdown sensitized cells to MAG-induced ferroptosis, while its overexpression restored SLC7A11/GPX4 expression and conferred resistance. Mechanistically, ETS2 transcriptionally regulated SLC7A11, and MAG enhanced ETS2-SLC7A11 protein interaction. In vivo, MAG significantly suppressed tumor growth with low toxicity and downregulated ETS2, SLC7A11, and GPX4.
MAG induces ferroptosis in MDA-MB-231 cells, which may be mediated by targeting the ETS2/SLC7A11/GPX4 signaling axis, providing mechanistic insights into its anti-TNBC activity.

PMID:
42602283
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.

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