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

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

Our most recent collaborative publication with following partners from the SPP 2306:

Marcel S. Woo, Ana J. Garcia-Saez, Manuel A. Friese and Marcus Conrad

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

Lorenz SM, Wahida A, Bostock MJ, Seibt T, Santos Dias Mourão A, Levkina A, Trümbach D, Soudy M, Emler D, Rothammer N, Woo MS, Sonner JK, Novikova M, Henkelmann B, Aldrovandi M, Kaemena DF, Mishima E, Vermonden P, Zong Z, Cheng D, Nakamura T, Ito J, Doll S, Proneth B, Bürkle E, Rizzollo F, Escamilla Ayala A, Napolitano V, Kolonko-Adamska M, Gaussmann S, Merl-Pham J, Hauck S, Pertek A, Orschmann T, van San E, Vanden Berghe T, Hass D, Maida A, Frenz JM, Pedrera L, Dolga A, Kraiger M, Hrabé de Angelis M, Fuchs H, Ebert G, Lenberg J, Friedman J, Scale C, Agostinis P, Zimprich A, Vogt-Weisenhorn D, Garrett L, Hölter SM, Wurst W, Glaab E, Lewerenz J, Popper B, Sieben C, Steinacker P, Zischka H, Garcia-Saez AJ, Tietze A, Ramesh SK, Ayton S, Vincendeau M, Friese MA, Wigby K, Sattler M, Mann M, Ingold I, Jayavelu AK, Popowicz GM, Conrad M.

Cell. 2025 Dec 4:S0092-8674(25)01310-8. doi: 10.1016/j.cell.2025.11.014. Online ahead of print. PMID: 41349546

Summary

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^R152H 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.