Ferroptosis是一种铁依赖性的细胞死亡程序，其特征为过度脂质过氧化。触发ferroptosis被提出作为一种有前途的抗癌策略，并能克服抗肿瘤治疗药物的耐药性。因此，了解引发ferroptosis化合物的分子相互作用和结构特征可能打开对抗侵袭性、转移性和对治疗抵抗的癌症的有效药理学策略的大门。我们在这里总结了针对ferroptosis中心作用因子的化合物的分子机制和结构要求，并着重介绍了（i）谷胱甘肽过氧化物酶（GPX）4，唯一能够解毒复杂的膜结合脂质过氧化物的GPX同工酶，（ii）半胱氨酸/谷氨酸反向转运体系统Xc - 中心作用于谷胱甘肽再生，（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的抑制与具有诱导作用的血红素氧化酶-1一同进行的血红素降解。我们推断了高效ferroptotic活性的共同特征，并强调了药物开发的挑战。此外，我们批判性地讨论了天然产物作为ferroptosis诱导剂的主导结构的潜力，并提供了结构多样的生物和生物启发的小分子的全面概述，这些小分子通过铁氧化、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来触发ferroptosis。© 2023 The Authors. Medicinal Research Reviews published by Wiley Periodicals LLC.

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 Xc - 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.© 2023 The Authors. Medicinal Research Reviews published by Wiley Periodicals LLC.