2. Academic Validation
  3. The NF-κB-SLC7A11 axis regulates ferroptosis sensitivity in inflammatory macrophages

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

  • Cell Insight. 2025 Jun 11;4(4):100257. doi: 10.1016/j.cellin.2025.100257.
Mengjie Yang 1 2,  Xiaowei Chen 2,  Xiran Hu 2,  Hexiang Li 2,  Hao Huang 2,  Yingzhe Fang 2,  Jue Jiang 3,  Hudan Liu 2 4,  Yuan Wang 5,  Guoliang Qing 1 2 4
Affiliations

Affiliations

  • 1 Department of Urology, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, Hubei, China.
  • 2 Frontier Science Center for Immunology and Metabolism, Medical research Institute, Wuhan University, Wuhan 430071, Hubei China.
  • 3 Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, Hubei, China.
  • 4 TaiKang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei, China.
  • 5 Department of Physiology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, Hubei, China.
PMID: 40677785 DOI: 10.1016/j.cellin.2025.100257
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.

Keywords

Ferroptosis; Immune metabolism; Macrophage; RELA; SLC7A11.

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