Oxyresveratrol as a novel ferroptosis inducer exhibits anticancer activity against breast cancer via the EGFR/PI3K/AKT/GPX4 signalling axis

作者：Lei Xiang, Qingzhou Li, Zhiwei Guan, Guilin Wang, Xiankuo Yu, Xianwen Zhang, Guochen Zhang, Jianguo Hu, Xue Yang, Mingrui Li, Xilinqiqige Bao, Yumei Wang, Dong Wang · 发表于：Frontiers in Pharmacology · 年份：2025 · DOI：10.3389/fphar.2024.1527286 · 被引用次数：14 · 研究领域：Ferroptosis and cancer prognosis、Cancer, Lipids, and Metabolism、Cancer-related molecular mechanisms research

Introduction Oxyresveratrol (ORes) exhibits significant anticancer activity, particularly against breast cancer. However, its exact mechanism of action (MOA) remains unclear. This study aimed to investigate the pharmacological activity and underlying MOA. Methods The inhibitory effect of ORes on breast cancer cell growth was confirmed, and the effective concentrations were determined for further experiments. Gene expression profiles (GEPs) were collected from MDA-MB-231 cells treated with ORes at varying concentrations using HTS 2 . Bioinformatics tools were used to predict the anticancer activity and MOA of ORes. Ferroptosis markers (ferrous ions, reactive oxygen species, lipid peroxidation, and GPX4 expression) were assessed, and mitochondrial morphology was observed. The effect of ORes on tumour growth was evaluated in vivo , along with the analysis of ferroptosis in tissues. The MOA was explored using L1000, Drug Gene DataBase (DGDB), and Western blotting analyses. Results ORes significantly reduces breast cancer cell viability and proliferation in a concentration-dependent manner, with IC 50 values of 104.8 μM, 150.2 μM, and 143.6 μM in MDA-MB-231, BT-549, and 4T1 cells, respectively. GEPs induced by ORes were significantly enriched in the ferroptosis and PI3K/AKT signalling pathways. ORes inhibited breast cancer cell growth, increased intracellular ferrous ion levels, reactive oxygen species, and lipid peroxidation, and induced ferroptosis-related mitochondrial alterati...