Michael Popp Institute, Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Tirol, Innsbruck, Austria.
Department of Molecular Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Thüringen, Jena, Germany.
Med Res Rev. 2023 May;43(3):614-682. doi: 10.1002/med.21933. Epub 2023 Jan 19.
Ferroptosis is an iron-dependent cell death program that is characterized by excessive lipid peroxidation. Triggering ferroptosis has been proposed as a promising strategy to fight cancer and overcome drug resistance in antitumor therapy. Understanding the molecular interactions and structural features of ferroptosis-inducing compounds might therefore open the door to efficient pharmacological strategies against aggressive, metastatic, and therapy-resistant cancer. We here summarize the molecular mechanisms and structural requirements of ferroptosis-inducing small molecules that target central players in ferroptosis. Focus is placed on (i) glutathione peroxidase (GPX) 4, the only GPX isoenzyme that detoxifies complex membrane-bound lipid hydroperoxides, (ii) the cystine/glutamate antiporter system X that is central for glutathione regeneration, (iii) the redox-protective transcription factor nuclear factor erythroid 2-related factor (NRF2), and (iv) GPX4 repression in combination with induced heme degradation via heme oxygenase-1. We deduce common features for efficient ferroptotic activity and highlight challenges in drug development. Moreover, we critically discuss the potential of natural products as ferroptosis-inducing lead structures and provide a comprehensive overview of structurally diverse biogenic and bioinspired small molecules that trigger ferroptosis via iron oxidation, inhibition of the thioredoxin/thioredoxin reductase system or less defined modes of action.
铁死亡是一种依赖铁的细胞死亡程序，其特征是脂质过氧化过度。触发铁死亡已被提议作为一种有前途的策略，以对抗癌症和克服抗肿瘤治疗中的耐药性。因此，了解诱导铁死亡的化合物的分子相互作用和结构特征可能为有效的药理学策略打开对抗侵袭性、转移性和治疗耐药性癌症的大门。我们在这里总结了靶向铁死亡中关键分子的诱导铁死亡的小分子的分子机制和结构要求。重点是 (i) 谷胱甘肽过氧化物酶 (GPX) 4，唯一能解毒复杂膜结合脂质过氧化物的 GPX 同工酶，(ii) 胱氨酸/谷氨酸反向转运系统 X，是谷胱甘肽再生的核心，(iii) 氧化还原保护转录因子核因子红细胞 2 相关因子 (NRF2)，以及 (iv) GPX4 抑制与通过血红素加氧酶-1 诱导的血红素降解相结合。我们推断出有效的铁死亡活性的共同特征，并强调药物开发中的挑战。此外，我们批判性地讨论了天然产物作为诱导铁死亡的先导结构的潜力，并提供了通过铁氧化、抑制硫氧还蛋白/硫氧还蛋白还原酶系统或不太明确的作用方式触发铁死亡的结构多样的生物源和仿生小分子的综合概述。
