Metabolic adaptations of inflammatory macrophages govern ferroptosis susceptibility via the GCH1–BH4–iNOS axis

Sauer J, Ogger PP, Dukic J, Nessensohn A, Gabler S, Schwenzer AK, Unsöld JK, Cortès BM, Steigenberger B, Fernandez Perez N, Strasser A, Dias Requiao R, Schleicher U, Griesser E, Bretschneider T, Gantner F, Thomas MJ, Watson CK, El Kasmi KC, Murray PJ (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Journal of Immunology American Association of Immunologists

Book Volume: 215

Article Number: vkag146

Journal Issue: 6

DOI: 10.1093/jimmun/vkag146

Abstract

In inflammatory tissue niches, macrophages encounter intense oxidative stress due to their own production of reactive oxygen and nitrogen species as part of antimicrobial defense. Our findings reveal that inflammatory macrophages deploy distinct, context-dependent redox-protective mechanisms to survive this self-inflicted stress, thereby avoiding ferroptotic cell death. Specifically, LPS-activated macrophages, M(LPS), rely on the GTP cyclohydrolase 1 (GCH1)–tetrahydrobiopterin (BH4) pathway for ferroptosis resistance, whereas LPS + IFN-γ–activated macrophages, M(LPS–IFN-γ), depend primarily on nitric oxide produced by inducible nitric oxide synthase (iNOS)—with the BH4 pathway suppressing cell death in the absence of nitric oxide. These distinct adaptations highlight a novel GCH1–BH4–iNOS axis that governs macrophage ferroptosis susceptibility. In both the LPS or the LPS + IFN-γ–activated settings, the redox-protective phenotype is reversible: Removal of inflammatory stimuli abolishes the protection, indicating that this metabolic programming requires continuous stimulation and is not a permanently fixed state. These findings uncover redox metabolism-guided metabolic distinctions between inflammatory macrophages and reveal how they preserve viability over prolonged inflammatory activation. Ultimately, our findings establish the GCH1–BH4–iNOS axis as a central, targetable mechanism to manipulate macrophage ferroptosis resistance for therapeutic purposes.

Authors with CRIS profile

Ulrike Schleicher Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene

Involved external institutions

Boehringer Ingelheim Pharma GmbH & Co. KG DE Germany (DE) Max-Planck-Institut für Biochemie / Max Planck Institute of Biochemistry DE Germany (DE) Universität Konstanz DE Germany (DE)

How to cite

APA:

Sauer, J., Ogger, P.P., Dukic, J., Nessensohn, A., Gabler, S., Schwenzer, A.K.,... Murray, P.J. (2026). Metabolic adaptations of inflammatory macrophages govern ferroptosis susceptibility via the GCH1–BH4–iNOS axis. Journal of Immunology, 215(6). https://doi.org/10.1093/jimmun/vkag146

MLA:

Sauer, Julia, et al. "Metabolic adaptations of inflammatory macrophages govern ferroptosis susceptibility via the GCH1–BH4–iNOS axis." Journal of Immunology 215.6 (2026).

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