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

Cell insight Pub Date : 2025-06-11 DOI:10.1016/j.cellin.2025.100257

Mengjie Yang , Xiaowei Chen , Xiran Hu , Hexiang Li , Hao Huang , Yingzhe Fang , Jue Jiang , Hudan Liu , Yuan Wang , Guoliang Qing

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Abstract

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.

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NF-κB-SLC7A11轴调节炎性巨噬细胞对铁下垂的敏感性

m1极化巨噬细胞表现出对铁凋亡的显著抵抗，铁凋亡是一种由过度脂质过氧化驱动的受调节细胞死亡形式。然而，其潜在机制仍有待确定。通过基于crispr的代谢基因功能筛选结合转录组学分析，我们发现胱氨酸/谷氨酸反转运蛋白SLC7A11是M1巨噬细胞嗜铁性耐药的关键介质。从机制上讲，脂多糖（LPS）与toll样受体4 （TLR4）结合导致NF-κB活化，导致rela依赖性Slc7a11表达的转录上调。SLC7A11反过来促进胱氨酸摄取和随后的谷胱甘肽（GSH）合成。基因消融Slc7a11减少GSH的产生，使M1巨噬细胞对rsl3诱导的铁凋亡敏感。总之，我们的研究结果揭示了RELA-SLC7A11轴作为一个关键的代谢检查点，决定巨噬细胞铁凋亡的敏感性，这可能被用来调节炎症性疾病中的巨噬细胞功能。

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