近日，德国代谢和细胞死亡研究所教授Marcus Conrad及其小组的研究开发出了GPX4中的鳍环样结构是铁死亡神经保护的基础。相关论文于2025年12月4日发表在《细胞》杂志上。
铁死亡是由膜磷脂不受控制的过氧化作用驱动的，与其他细胞死亡方式不同，因为它缺乏启动信号，并受到内源性抗氧化防御的监视。谷胱甘肽过氧化物酶4 （GPX4）是铁死亡的守护者，尽管其膜保护功能尚不清楚。对GPX4 （p.R152H）中引起早发性神经变性的错义突变的结构和功能分析表明，这种变异破坏了膜锚定，但不会显著损害其催化活性。
小鼠时空Gpx4缺失或神经元特异性GPX4R152H表达诱导皮质和小脑神经元变性，并伴有进行性神经炎症。患者诱导的多能干细胞（iPSC）衍生的皮质神经元和前脑类器官显示出增加的铁死亡易感性，反映了关键的病理特征，并且对铁死亡抑制敏感。神经蛋白质组学在受影响的大脑中发现了类似阿尔茨海默病的特征。这些发现强调了适当的GPX4膜锚定的必要性，确立了铁死亡是神经退行性疾病的关键驱动因素，并为将铁死亡作为神经退行性疾病的治疗策略提供了依据。
附：英文原文
Title: A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis
Author: Svenja M. Lorenz, Adam Wahida, Mark J. Bostock, Tobias Seibt, André Santos Dias Mouro, Anastasia Levkina, Dietrich Trümbach, Mohamed Soudy, David Emler, Nicola Rothammer, Marcel S. Woo, Jana K. Sonner, Mariia Novikova, Bernhard Henkelmann, Maceler Aldrovandi, Daniel F. Kaemena, Eikan Mishima, Perrine Vermonden, Zhi Zong, Deng Cheng, Toshitaka Nakamura, Junya Ito, Sebastian Doll, Bettina Proneth, Erika Bürkle, Francesca Rizzollo, Abril Escamilla Ayala, Valeria Napolitano, Marta Kolonko-Adamska, Stefan Gaussmann, Juliane Merl-Pham, Stefanie Hauck, Anna Pertek, Tanja Orschmann, Emily van San, Tom Vanden Berghe, Daniela Hass, Adriano Maida, Joris M. Frenz, Lohans Pedrera, Amalia Dolga, Markus Kraiger, Martin Hrabé de Angelis, Helmut Fuchs, Gregor Ebert, Jerica Lenberg, Jennifer Friedman, Carolin Scale, Patrizia Agostinis, Annemarie Zimprich, Daniela Vogt-Weisenhorn, Lillian Garrett, Sabine M. Hlter, Wolfgang Wurst, Enrico Glaab, Jan Lewerenz, Bastian Popper, Christian Sieben, Petra Steinacker, Hans Zischka, Ana J. Garcia-Saez, Anna Tietze, Sanath Kumar Ramesh
Issue&Volume: 2025-12-04
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 GPX4R152H 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.
DOI: 10.1016/j.cell.2025.11.014
Source: https://www.cell.com/cell/abstract/S0092-8674(25)01310-8