Yang Mengjie, Chen Xiaowei, Hu Xiran, Li Hexiang, Huang Hao, Fang Yingzhe, Jiang Jue, Liu Hudan, Wang Yuan, Qing Guoliang
Department of Urology, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, Hubei, China.
Frontier Science Center for Immunology and Metabolism, Medical research Institute, Wuhan University, Wuhan 430071, Hubei China.
Cell Insight. 2025 Jun 11;4(4):100257. doi: 10.1016/j.cellin.2025.100257. eCollection 2025 Aug.
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 expression. SLC7A11 in turn promoted cystine uptake and subsequent glutathione (GSH) synthesis. Genetic ablation of 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.
M1极化的巨噬细胞对铁死亡表现出显著抗性，铁死亡是一种由过度脂质过氧化驱动的程序性细胞死亡形式。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并结合转录组学分析，我们在此确定了胱氨酸/谷氨酸反向转运体SLC7A11是M1巨噬细胞中铁死亡抗性的关键介质。从机制上讲，脂多糖（LPS）与Toll样受体4（TLR4）结合导致NF-κB激活，从而导致RELA依赖的SLC7A11表达转录上调。SLC7A11进而促进胱氨酸摄取及随后的谷胱甘肽（GSH）合成。SLC7A11基因缺失降低了GSH生成，使M1巨噬细胞对RSL3诱导的铁死亡敏感。总之，我们的研究结果揭示了RELA-SLC7A11轴是决定巨噬细胞铁死亡敏感性的关键代谢检查点，这可能用于调节炎症性疾病中的巨噬细胞功能。
