叔丁基氢过氧化物 (t-BuOOH) 是一种有机氢过氧化物，广泛用作诱导氧化应激的模型化合物。它会导致大量细胞损伤，包括脂质过氧化、DNA 双链断裂 (DNA DSB) 和线粒体膜电位 (MMP) 破坏。我们可以在几种细胞系中证明，t-BuOOH 会诱导铁死亡，这是由铁依赖性脂质过氧化引发的。我们进一步揭示，细胞与细胞的接触不仅可以​​防止 t-BuOOH 介导的铁死亡，而且可以防止 DNA DSB 和 MMP 的丢失。根本机制尚不清楚。在这里，我们在小鼠成纤维细胞和人结肠癌细胞系中证明，t-BuOOH（分别为 50 或 100 µM）会导致细胞内 Ca2+ 增加，并且这种增加是脂质过氧化和铁死亡、DNA DSB 形成和MMP 的耗散。我们进一步证明细胞与细胞的接触可以防止 t-BuOOH 介导的细胞内 Ca2+ 升高。因此，我们对 t-BuOOH 触发的细胞损伤（包括铁死亡）的机制提供了新的见解，并提出了一种模型，其中细胞-细胞接触控制细胞内 Ca2+ 水平，以防止脂质过氧化、DNA DSB 形成和 MMP 损失。由于 Ca2 是响应氧化应激的毒性的核心参与者，并且参与各种细胞死亡途径，因此我们的观察表明细胞与细胞接触对各种外源毒物具有广泛的保护功能。© 2024。作者。

Tert-butyl hydroperoxide (t-BuOOH) is an organic hydroperoxide widely used as a model compound to induce oxidative stress. It leads to a plethora of cellular damage, including lipid peroxidation, DNA double-strand breaks (DNA DSBs), and breakdown of the mitochondrial membrane potential (MMP). We could show in several cell lines that t-BuOOH induces ferroptosis, triggered by iron-dependent lipid peroxidation. We have further revealed that not only t-BuOOH-mediated ferroptosis, but also DNA DSBs and loss of MMP are prevented by cell-cell contacts. The underlying mechanisms are not known. Here, we show in murine fibroblasts and a human colon carcinoma cell line that t-BuOOH (50 or 100 µM, resp.) causes an increase in intracellular Ca2+, and that this increase is key to lipid peroxidation and ferroptosis, DNA DSB formation and dissipation of the MMP. We further demonstrate that cell-cell contacts prevent t-BuOOH-mediated raise in intracellular Ca2+. Hence, we provide novel insights into the mechanism of t-BuOOH-triggered cellular damage including ferroptosis and propose a model in which cell-cell contacts control intracellular Ca2+ levels to prevent lipid peroxidation, DNA DSB-formation and loss of MMP. Since Ca2+ is a central player of toxicity in response to oxidative stress and is involved in various cell death pathways, our observations suggest a broad protective function of cell-cell contacts against a variety of exogenous toxicants.© 2024. The Author(s).