A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis

Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant disrupts membrane anchoring without considerably impairing its catalytic activity. Spatiotemporal Gpx4 deletion or neuron-specific GPX4<sup>R152H</sup> expression in mice induced degeneration of cortical and cerebellar neurons, accompanied by progressive neuroinflammation. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids displayed increased ferroptotic vulnerability, mirroring key pathological features, and were sensitive to ferroptosis inhibition. Neuroproteomics revealed Alzheimer's-like signatures in affected brains. These findings highlight the necessity of proper GPX4 membrane anchoring, establish ferroptosis as a key driver of neurodegeneration, and provide the rationale for targeting ferroptosis as a therapeutic strategy in neurodegenerative disease.

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Journal
Cell
Published
2025-12-04
DOI
https://doi.org/10.1016/j.cell.2025.11.014
Citations
8
Primary Topic
Ferroptosis and cancer prognosis
Type
article
Field-Weighted Citation Impact
12.15
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article

A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis

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A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis

Annemarie Zimprich, Martin Hrabě de Angelis, Grzegorz M. Popowicz, Jan Lewerenz, Juliane Merl‐Pham, Anastasia Levkina, Daniela Hass, Dietrich Trümbach, Sebastian Doll, Anna Pertek, Marta Kolonko, Mark J. Bostock, Tanja Orschmann, Manuel Alexander Friese, Helmut Fuchs, Cheng Dan Deng, Emily Van San, Scott Ayton, Daniel F. Kaemena, Nicola Rothammer, Bastian Popper, Lohans Pedrera, Stefan Gaussmann, Stefanie M. Hauck, Mohamed Soudy, Markus Kraiger, Wolfgang Wurst, Svenja Lorenz, André Mourão, Valeria Napolitano, Marcus Conrad, Marcel S. Woo, Abril Escamilla‐Ayala, Bettina Proneth, Ashok Kumar Jayavelu, Ana J. García‐Sáez, Christian Sieben, Hans Zischka, Michelle Vincendeau, Michael Sattler, Kristen M. Wigby, Bernhard Henkelmann, Junya Ito, Sabine M. Hölter, Enrico Glaab, Toshitaka Nakamura, Francesca Rizzollo, Amalia M. Dolga, Gregor Ebert, Perrine Vermonden, Sanath Kumar Ramesh, Jana K. Sonner, Daniela M. Vogt Weisenhorn, Eikan Mishima, Tobias Seibt, Maceler Aldrovandi, Jennifer Friedman, Lillian Garrett, Adriano Maida, Adam Wahida, Anna Tietze, Petra Steinacker, Tom Vanden Berghe, Jerica Lenberg, Irina Ingold, J. Frenz, Patrizia Agostinis, David Emler, Zhi Zong, Mariia Novikova, Matthias Mann, Erika Bürkle, Carolin Scale
article en
8 citations

Abstract

Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant disrupts membrane anchoring without considerably impairing its catalytic activity. Spatiotemporal Gpx4 deletion or neuron-specific GPX4<sup>R152H</sup> expression in mice induced degeneration of cortical and cerebellar neurons, accompanied by progressive neuroinflammation. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids displayed increased ferroptotic vulnerability, mirroring key pathological features, and were sensitive to ferroptosis inhibition. Neuroproteomics revealed Alzheimer's-like signatures in affected brains. These findings highlight the necessity of proper GPX4 membrane anchoring, establish ferroptosis as a key driver of neurodegeneration, and provide the rationale for targeting ferroptosis as a therapeutic strategy in neurodegenerative disease.

CellVol. 189(1)
University of Antwerp (BE), Universität Hamburg (DE), University of Groningen (NL), University of Luxembourg (LU), Universität Ulm (DE), Helmholtz Zentrum München (DE), University Medical Center Hamburg-Eppendorf (DE), Helmholtz Centre for Infection Research (DE), Target (Germany) (DE), Max Planck Institute of Biochemistry (DE)
Openalex Percentile: Top 1%
Ferroptosis and cancer prognosis
12.15
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