Roeck Bernhard F, Lotfipour Nasudivar Sara, Vorndran Michael R H, Schueller Lena, Yapici F Isil, Rübsam Matthias, von Karstedt Silvia, Niessen Carien M, Garcia-Saez Ana J
Institute for Genetics, University of Cologne, Cologne, Germany.
CECAD Cluster of Excellence, University of Cologne, Cologne, Germany.
Nat Commun. 2025 Mar 26;16(1):2951. doi: 10.1038/s41467-025-58175-w.
Ferroptosis is a lytic, iron-dependent form of regulated cell death characterized by excessive lipid peroxidation and associated with necrosis spread in diseased tissues through unknown mechanisms. Using a novel optogenetic system for light-driven ferroptosis induction via degradation of the anti-ferroptotic protein GPX4, we show that lipid peroxidation and ferroptotic death can spread to neighboring cells through their closely adjacent plasma membranes. Ferroptosis propagation is dependent on cell distance and completely abolished by disruption of α-catenin-dependent intercellular contacts or by chelation of extracellular iron. Remarkably, bridging cells with a lipid bilayer or increasing contacts between neighboring cells enhances ferroptosis spread. Reconstitution of iron-dependent spread of lipid peroxidation between pure lipid, contacting liposomes provides evidence for the physicochemical mechanism involved. Our findings support a model in which iron-dependent lipid peroxidation propagates across proximal plasma membranes of neighboring cells, thereby promoting the transmission of ferroptotic cell death with consequences for pathological tissue necrosis spread.
铁死亡是一种溶解性的、铁依赖性的程序性细胞死亡形式，其特征是脂质过氧化过度，并通过未知机制与病变组织中的坏死扩散相关。我们使用一种新型光遗传学系统，通过降解抗铁死亡蛋白GPX4来诱导光驱动的铁死亡，结果表明脂质过氧化和铁死亡可以通过相邻的质膜扩散到邻近细胞。铁死亡的传播取决于细胞间距离，通过破坏α-连环蛋白依赖性细胞间接触或螯合细胞外铁可完全消除这种传播。值得注意的是，用脂质双层连接细胞或增加相邻细胞之间的接触可增强铁死亡的扩散。在纯脂质、接触脂质体之间重建铁依赖性脂质过氧化的扩散，为其中涉及的物理化学机制提供了证据。我们的研究结果支持一种模型，即铁依赖性脂质过氧化在相邻细胞的近端质膜间传播，从而促进铁死亡性细胞死亡的传递，对病理性组织坏死的扩散产生影响。
