铁死亡是一种脂质过氧化驱动的细胞死亡程序，受到谷胱甘肽过氧化物酶 4 和内源性氧化还原循环的控制，有望为治疗难治性癌症提供新的策略。氯代[N,N'-二水杨基-1,2-苯二胺]铁 (III) 络合物 (SC) 通过仍知之甚少的分子机制诱导铁死亡、细胞凋亡或坏死性凋亡，从而具有有效的抗癌特性。在这里，我们表明，在三阴性乳腺癌细胞 (LC50 ≥ 0.07 μM) 中，SC 比其他细胞死亡程序优先诱导铁死亡，并且对具有获得性侵袭性、化学或放射抗性的细胞系特别有效。氧化还原脂质组学揭示细胞死亡的启动与膜磷脂（特别是磷脂酰乙醇胺和磷脂酰肌醇）中花生四烯酸和肾上腺酸的广泛（氢过）氧化有关，且 SC 的表现优于已建立的铁死亡诱导剂。从机理上讲，SCs 可能通过氧化还原循环有效催化单电子转移反应，其中涉及 Fe(III) 还原为 Fe(II) 物质以及氧桥二聚复合物的可逆形成，这一点得到循环伏安法的支持。因此，SCs 可以利用过氧化氢产生有机自由基，但不能产生羟基自由基，并氧化膜磷脂和（膜）保护因子，例如 NADPH（细胞中的 NADPH）。我们得出的结论是，SC 催化特定的氧化还原反应，驱动膜过氧化，同时干扰细胞（包括耐药癌细胞）解毒磷脂氢过氧化物的能力。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Ferroptosis, a lipid peroxidation-driven cell death program kept in check by glutathione peroxidase 4 and endogenous redox cycles, promises access to novel strategies for treating therapy-resistant cancers. Chlorido [N,N'-disalicylidene-1,2-phenylenediamine]iron (III) complexes (SCs) have potent anti-cancer properties by inducing ferroptosis, apoptosis, or necroptosis through still poorly understood molecular mechanisms. Here, we show that SCs preferentially induce ferroptosis over other cell death programs in triple-negative breast cancer cells (LC50 ≥ 0.07 μM) and are particularly effective against cell lines with acquired invasiveness, chemo- or radioresistance. Redox lipidomics reveals that initiation of cell death is associated with extensive (hydroper)oxidation of arachidonic acid and adrenic acid in membrane phospholipids, specifically phosphatidylethanolamines and phosphatidylinositols, with SCs outperforming established ferroptosis inducers. Mechanistically, SCs effectively catalyze one-electron transfer reactions, likely via a redox cycle involving the reduction of Fe(III) to Fe(II) species and reversible formation of oxo-bridged dimeric complexes, as supported by cyclic voltammetry. As a result, SCs can use hydrogen peroxide to generate organic radicals but not hydroxyl radicals and oxidize membrane phospholipids and (membrane-)protective factors such as NADPH, which is depleted from cells. We conclude that SCs catalyze specific redox reactions that drive membrane peroxidation while interfering with the ability of cells, including therapy-resistant cancer cells, to detoxify phospholipid hydroperoxides.Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.