The NF-κB-SLC7A11 axis regulates ferroptosis sensitivity in inflammatory macrophages

作者：Mengjie Yang, Xiaowei Chen, Xin Hu, Hexiang Li, Hao Huang, Yingzhe Fang, Jue Jiang, Hudan Liu, Yuan Wang, Guoliang Qing · 发表于：Cell Insight · 年份：2025 · DOI：10.1016/j.cellin.2025.100257 · 被引用次数：15 · 研究领域：Ferroptosis and cancer prognosis、Cancer-related molecular mechanisms research、Circular RNAs in diseases

M1-polarized macrophages exhibit remarkable resistance to ferroptosis, a form of regulated cell death driven by excessive lipid peroxidation. Yet the underlying mechanisms remain to be defined. Through CRISPR-based functional screen of metabolic genes combining transcriptomics analysis, we herein identified the cystine/glutamate antiporter SLC7A11 as a pivotal mediator of ferroptosis resistance in M1 macrophages. Mechanistically, lipopolysaccharide (LPS) engagement with the Toll-like receptor 4 (TLR4) resulted in NF-κB activation, leading to RELA-dependent transcriptional upregulation of Slc7a11 expression. SLC7A11 in turn promoted cystine uptake and subsequent glutathione (GSH) synthesis. Genetic ablation of Slc7a11 reduced GSH production, sensitizing M1 macrophages to RSL3-induced ferroptosis. In aggregate, our findings unveil the RELA-SLC7A11 axis as a critical metabolic checkpoint dictating macrophage ferroptosis sensitivity, which might be employed to modulate macrophage functions in inflammatory diseases.