Exploiting metabolic vulnerabilities through synergistic ferroptosis and disulfidptosis for breast cancer therapy

作者：Yu Liang, Haibo Lan, Qiuyu Li, Mengdan Gao, Minyi Liu, Ziting Xu, Yang Gao, Li Zhang, Yingjia Li, Bingxia Zhao · 发表于：Journal of Advanced Research · 年份：2025 · DOI：10.1016/j.jare.2025.03.052 · 被引用次数：23 · 研究领域：Ferroptosis and cancer prognosis、Immune cells in cancer、Cancer, Lipids, and Metabolism

INTRODUCTION: Ferroptosis represents a promising therapeutic approach for breast cancer treatment. However, cancer cells can develop resistance through the SLC7A11-GSH-GPX4 axis, wherein increased SLC7A11 expression enhances cystine uptake, replenishes GSH, and reactivates GPX4. Notably, cells with high SLC7A11 expression become vulnerable to disulfidptosis under glucose-deprived conditions. OBJECTIVES: We aimed to develop a dual-mode therapeutic strategy that simultaneously induces ferroptosis and disulfidptosis by targeting both lipid peroxidation and glucose metabolism in breast cancer cells. METHODS: Fe-Cu-SS metal-organic frameworks (MOFs) loaded with BAY876 (FCSP@876 MOFs) were synthesized to enhance ferroptosis and trigger disulfidptosis in breast cancer cells. The MOFs were characterized using transmission electron microscopy (TEM), Fourier-transform infrared (FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), and UV-Vis spectroscopy. In vitro experiments demonstrated that FCSP@876 MOFs increased reactive oxygen species (ROS) levels and lipid peroxidation while depleting NADPH. Western blotting and actin filament staining confirmed the underlying mechanisms. In vivo xenograft experiments in BALB/c mice assessed the synergistic effects of ferroptosis and disulfidptosis induction. RESULTS: During ferroptosis induction, cancer cells exhibited an adaptive upregulation of SLC7A11 expression. FCSP@876 MOFs effectively counteracted this resistance mechanism by simul...