Hemin is a protoporphyrin complex of ferric ion which catalyzes H₂O₂ degradation and produces reactive oxygen species (ROS). This ROS generation property induces oxidative stress to hemin-exposed cells that can lead to various situations such as intracellular Fenton reaction, ferroptosis, or autophagy. Therapeutic performance of hemin is hindered due to low bioavailability of the active monomeric form with an intact ROS generation property. Here, we demonstrate a colloidal nanoparticle form of hemin (nano-hemin) with a high ROS generation property and high cell uptake property. We have shown that nano-hemin produces ROS inside a cell that upregulate heme oxygenase-1 in order to metabolize hemin. This leads to the ferroptosis-mediated cell death. Furthermore, we show that the ROS generation property of nano-hemin can be modulated to control hemin cytotoxicity for either ferroptosis or autophagy. Our findings suggest that nano-hemin can be designed with modular cytotoxicity for different therapeutic applications.

中文翻译：

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通过酶促血红素消化为铁死亡介导的细胞死亡设计纳米血红素


血红素是铁离子的原卟啉络合物，可催化 H₂O₂ 降解并产生活性氧 （ROS）。这种 ROS 生成特性会诱导血红素暴露细胞的氧化应激，从而导致各种情况，例如细胞内 Fenton 反应、铁死亡或自噬。由于具有完整 ROS 生成特性的活性单体形式的生物利用度低，血红素的治疗性能受到阻碍。在这里，我们展示了血红素 （nano-hemin） 的胶体纳米颗粒形式，具有高 ROS 生成特性和高细胞摄取特性。我们已经证明，纳米血红素在细胞内产生 ROS，上调血红素加氧酶-1 以代谢血红素。这导致铁死亡介导的细胞死亡。此外，我们表明纳米血红素的 ROS 生成特性可以被调节以控制血红素对铁死亡或自噬的血红素细胞毒性。我们的研究结果表明，纳米血红素可以设计为具有模块化细胞毒性的纳米血红素，用于不同的治疗应用。