我们设计了一种基于三邻苯二酚的铁载体模拟物 H6-T-CATL，用于选择性地螯合线粒体细胞色素和细胞基质内其他含铁蛋白质中的铁 (III)。这种策略性封存的目的是通过谷胱甘肽 (GSH) 依赖性还原铁的释放以及随后的 ROS 介导的细胞毒性来触发癌细胞凋亡或铁死亡。 H6-T-CATL 的合成涉及精确的肽偶联反应。使用类似于细胞色素 c 的 Fe(III)-卟啉模型 (Fe-TPP-Cl)，我们研究了 H6-T-CATL 提取铁 (III) 的能力，所得铁的结合常数 (Krel) 为 1014 (III)络合物(FeIII-T-CATL)3-。该复合物很容易经历谷胱甘肽介导的还原反应，释放出生物可利用的铁 (II)，后者催化类芬顿反应产生羟基自由基 (˙OH)，这一点已通过光谱分析得到证实。我们的研究强调了 H6-T-CATL 通过消耗细胞金属蛋白中的铁 (III)、释放促凋亡铁 (II) 来诱导癌细胞死亡的潜力。对包括正常细胞在内的各种癌症类型的评估表明，H6-T-CATL 通过 ROS 产生、线粒体功能障碍以及铁死亡和 DNA 损伤途径的激活而具有细胞毒性。这些发现提出了一种新的癌症治疗机制，利用细胞内的内源性铁储备。 H6-T-CATL 成为一种有前途的下一代抗癌剂，利用铁代谢的脆弱性，通过诱导铁死亡来诱导选择性癌细胞死亡。

We designed a tris-catecholate-based siderophore mimic, H6-T-CATL, to selectively chelate iron(III) from mitochondrial cytochromes and other iron-containing proteins within cellular matrices. This strategic sequestration aims to trigger apoptosis or ferroptosis in cancer cells through the glutathione (GSH)-dependent release of reduced iron and subsequent ROS-mediated cytotoxicity. Synthesis of H6-T-CATL involved precise peptide coupling reactions. Using the Fe(III)-porphyrin model (Fe-TPP-Cl), akin to cytochrome c, we studied H6-T-CATL's ability to extract iron(III), yielding a binding constant (Krel) of 1014 for the resulting iron(III) complex (FeIII-T-CATL)3-. This complex readily underwent GSH-mediated reduction to release bioavailable iron(II), which catalyzed Fenton-like reactions generating hydroxyl radicals (˙OH), confirmed by spectroscopic analyses. Our research underscores the potential of H6-T-CATL to induce cancer cell death by depleting iron(III) from cellular metalloproteins, releasing pro-apoptotic iron(II). Evaluation across various cancer types, including normal cells, demonstrated H6-T-CATL's cytotoxicity through ROS production, mitochondrial dysfunction, and activation of ferroptosis and DNA damage pathways. These findings propose a novel mechanism for cancer therapy, leveraging endogenous iron stores within cells. H6-T-CATL emerges as a promising next-generation anticancer agent, exploiting iron metabolism vulnerabilities to induce selective cancer cell death through ferroptosis induction.