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

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

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 id...

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Bibliographic Details
Main Authors: Mengjie Yang, Xiaowei Chen, Xiran Hu, Hexiang Li, Hao Huang, Yingzhe Fang, Jue Jiang, Hudan Liu, Yuan Wang, Guoliang Qing
Format: Article
Language:English
Published: Elsevier 2025-08-01
Series:Cell Insight
Subjects:
Macrophage
Ferroptosis
SLC7A11
RELA
Immune metabolism
Online Access:http://www.sciencedirect.com/science/article/pii/S2772892725000318
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Summary: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.
ISSN:2772-8927

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