2. Academic Validation
  3. Tolerance to ferroptosis facilitates lipid metabolism and pathogenic type 2 immunity in allergic airway inflammation

Tolerance to ferroptosis facilitates lipid metabolism and pathogenic type 2 immunity in allergic airway inflammation

  • Immunity. 2025 Dec 10:S1074-7613(25)00520-5. doi: 10.1016/j.immuni.2025.11.018.
Chantal Wientjens 1,  Maria Doverman 1,  Jelena Zurkovic 2,  Tushar More 3,  Jayagopi Surendar 1,  Svetozar Nesic 4,  Carola Sarici 1,  Timon D Utecht 1,  Johanna Pohl 1,  Jonathan Pollock 5,  David Voehringer 5,  Karsten Hiller 3,  Christoph Thiele 2,  Christoph Wilhelm 6
Affiliations

Affiliations

  • 1 Immunopathology Unit, Institute of Clinical Chemistry and Clinical Pharmacology, Medical Faculty, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany.
  • 2 Life & Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany.
  • 3 Department of Bioinformatics and Biochemistry, Braunschweig Integrated Center of Systems Biology, Technische Universität Braunschweig, Brunswick, Germany.
  • 4 Institute for Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany; Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany.
  • 5 Department of Infection Biology, University Hospital Erlangen, 91054 Erlangen, Germany; Profile Center Immunomedicine (FAU-i-MED), Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
  • 6 Immunopathology Unit, Institute of Clinical Chemistry and Clinical Pharmacology, Medical Faculty, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany. Electronic address: [email protected].
PMID: 41380684 DOI: 10.1016/j.immuni.2025.11.018
Abstract

Type 2 innate lymphoid cells (ILC2s) are essential for maintaining and protecting barrier tissues, but they also drive chronic inflammation, a process associated with altered metabolic activity. Identifying and targeting the metabolic pathways driving ILC2-mediated inflammation could restore tissue homeostasis. Here, we find that in allergic airway inflammation, pathogenic ILC2s rely on cystine for enhanced metabolic flexibility and survival. Cystine acquisition fuels glutathione (GSH) synthesis, which, together with increased expression of Glutathione Peroxidase 4 (GPX4) and thioredoxin reductase 1 (TXNRD1), confers resistance to Ferroptosis by counteracting lipid peroxidation and Reactive Oxygen Species (ROS). This adaptation enables accelerated lipid acquisition and metabolism, fostering ILC2 and T helper type 2 (Th2) cell expansion. Conversely, ablation of GPX4 and TXNRD1 in ILC2s or pharmacological inhibition of TXNRD1 constrains lipid metabolism and prevents ILC2 accumulation in allergen-induced airway inflammation. This demonstrates that increased reliance on antioxidant systems represents a metabolic vulnerability that can be exploited therapeutically to treat asthma.

Keywords

GPX4; ILC2; ROS; asthma; cysteine; fatty acids; ferroptosis; innate lymphoid cells; lipid metabolism; thioredoxin.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-125006
    99.69%, TXNRD1 Inhibitor