Matrine targets β-catenin and blocks the formation of β-catenin/TCF7L2 complex to promote ferroptosis and inhibit metastasis in triple-negative breast cancer

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-07-06 DOI:10.1016/j.phymed.2025.157044

Yazhou Sang , Yue Hu , Ruohan Liang , Yueyue Zhang , Hongyuan Du , Huilan Zhang , Juan Chen , Yaqiong Zhang , Xuan Cao

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引用次数: 0

Abstract

Background

Triple-negative breast cancer (TNBC) is still incurable, exhibiting a high propensity for metastasis. Matrine has been confirmed to possess anti-tumor properties. Nevertheless, the precise mechanism by which matrine inhibits TNBC metastasis remains uncertain.

Purpose

This investigation aimed to explore whether matrine could disrupt TNBC metastasis.

Methods

The migratory capacity of TNBC cells was assessed via wound healing and transwell assays. Then, we evaluated whether matrine directly interacts with β-catenin (β-cat). Molecular docking combined with plasmid point mutation was employed to ascertain the specific amino acid binding sites of matrine and β-cat. Next, we evaluated the impact of matrine on the formation of β-cat/transcription factor 7 like 2 (TCF7L2) complex and whether matrine could induce ferroptosis (FPT) in TNBC. The mouse lung metastasis model was utilized to assess the potential of matrine in inhibiting TNBC metastasis.

Results

Our research proved that matrine could directly target β-cat and abrogate the interaction of β-cat and TCF7L2, thus inhibiting the Wnt/β-cat downstream signaling pathway. Furthermore, matrine weakened the regulatory effect of TCF7L2 on glutathione peroxidase 4 (GPX4) and enhanced FPT by hindering the formation of the β-cat/TCF7L2 transcription complex. In addition, matrine-induced FPT effectively suppressed epithelial-mesenchymal transition (EMT) in TNBC.

Conclusions

This study demonstrates that matrine impedes the stimulation of the Wnt/β-cat pathway, has anti-metastatic effects on TNBC by triggering ferroptosis and inhibiting EMT.

Abstract Image

查看原文本刊更多论文

苦参碱以β-catenin为靶点，阻断β-catenin/TCF7L2复合物的形成，促进三阴性乳腺癌铁下垂，抑制转移

背景三阴性乳腺癌（TNBC）仍然是无法治愈的，表现出很高的转移倾向。苦参碱已被证实具有抗肿瘤的特性。然而，苦参碱抑制TNBC转移的确切机制仍不确定。目的探讨苦参碱对TNBC转移的影响。方法采用创面愈合法和经孔法观察TNBC细胞的迁移能力。然后，我们评估了苦参碱是否直接与β-catenin （β-cat）相互作用。采用分子对接结合质粒点突变的方法确定了苦参碱和β-cat的特异性氨基酸结合位点。接下来，我们评估了苦参碱对β-cat/转录因子7 like 2 （TCF7L2）复合物形成的影响，以及苦参碱是否会诱导TNBC中的铁ptosis （FPT）。采用小鼠肺转移模型评价苦参碱抑制TNBC转移的潜力。结果我们的研究证明苦参碱可以直接靶向β-cat，阻断β-cat与TCF7L2的相互作用，从而抑制Wnt/β-cat下游信号通路。此外，苦参碱通过抑制β-cat/TCF7L2转录复合物的形成，减弱了TCF7L2对谷胱甘肽过氧化物酶4 （GPX4）的调控作用，提高了FPT。此外，雌性激素诱导的FPT可有效抑制TNBC的上皮-间质转化（EMT）。结论本研究表明苦参碱抑制Wnt/β-cat通路的刺激，通过触发铁凋亡和抑制EMT对TNBC具有抗转移作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.