Non-neuronal ferroptosis in the central nervous system

Abstract

Ferroptosis, a lipid peroxidation-driven form of regulated cell death, has emerged as a central mechanism in neurological disease. While most studies have focused on neuronal vulnerability, non-neuronal cells, including oligodendrocytes, astrocytes, microglia, brain endothelial cells, and central nervous system (CNS) infiltrating T cells, play equally critical roles in shaping disease progression. These cell types regulate iron homeostasis, lipid metabolism, antioxidant defenses, and inflammatory signaling, thereby establishing the microenvironmental conditions that determine ferroptotic susceptibility within the CNS. Accumulating evidence demonstrates lipid peroxidation and ferroptosis-related signaling in demyelinating disorders, ischemic injury, small vessel disease, Alzheimer’s disease, Parkinson’s disease, and spinal cord injury. However, the contribution of non-neuronal cells to ferroptotic stress and execution remains comparatively underexplored. In this review, we synthesize emerging data highlighting cell type-specific dependencies on glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), ferroptosis suppressor protein 1 (FSP1), nuclear factor erythroid 2-related factor 2 (NRF2), peroxiredoxin (PRDX), thioredoxin (TRX), iron-handling proteins, and lipid remodeling pathways, and discuss how these regulatory networks differ across CNS-resident and CNS infiltrating T cells. We propose that ferroptosis in neurological disease is not solely a neuron-autonomous event, but a tissue-level process orchestrated by non-neuronal cells with distinct metabolic and immunological programs. Understanding these cell type-specific vulnerabilities and regulatory mechanisms will be essential for the development of targeted therapeutic strategies aimed at modulating ferroptotic stress in neuroinflammatory and neurodegenerative disorders.

Keywords

Neurodegeneration / neuroinflammation / glia cells / immune cells / endothelial cells

Acknowledgements

The figures in the manuscript were generated using biorender. During the preparation of this work, the authors used generative AI (ChatGPT, OpenAI, GPT-5.5) solely to improve the language, grammar, and readability of the text. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the final output.

Authors contribution

Winneberger J: Visualization, investigation, writing-original draft. Raich L: Investigation, writing-original draft. Potthast T: Investigation. Woo MS: Investigation, supervision, funding acquisition, writing-original draft. All authors agree to the final version of the manuscript.

Conflicts of interest

The authors disclose no competing interests.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This research is supported by the German Research Foundation (WO 2835/1-1 to MSW) and Corona Foundation (S0199/10110/2025 to MSW).

Copyright

© The Author(s) 2026.

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