铁死亡是一种由铁依赖性脂质过氧化物积累驱动的受调节细胞死亡。铁死亡在多种人类疾病中的高度参与突出表明需要鉴定具有抗铁死亡活性的新化学型。在这里，我们在 HT1080 纤维肉瘤细胞中进行了天然产物库筛选，并鉴定了甘草查耳酮 A (LA)、乙酸异丁香酯 (ISA) 和异莲心碱 (ISL) 作为 RSL3 或 IKE 诱导的铁死亡的抑制剂。从机制上讲，这些化合物赋予的铁死亡抗性主要是通过 GPX4/NRF2 独立机制实现的。其中，只有ISL能够有效挽救FINO2（亚铁的稳定氧化剂）诱导的铁死亡，这表明ISL可能具有铁螯合剂的特性。与假设一致，计算工具和 X 射线光电子能谱都支持 ISL 和铁离子之间的结合。 ISL 通过限制细胞内铁积累，极大地抑制了过度的铁依赖性铁死亡细胞死亡。此外，其铁螯合剂活性还可以保护小鼠在急性铁过载模型中免受器官损伤。总之，这项研究为从天然产物中开发有效的抗铁死亡药物提供了宝贵的见解，这代表了治疗铁死亡相关器官损伤的潜在治疗策略。

Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of lipid peroxides. The high involvement of ferroptosis in diverse human diseases highlights the need for the identification of new chemotypes with anti-ferroptotic activity. Here, we performed a natural product library screening in HT1080 fibrosarcoma cells and identified licochalcone A (LA), isoeugenyl acetate (ISA), and isoliensinine (ISL) as suppressors of either RSL3- or IKE-induced ferroptosis. Mechanistically, ferroptosis resistance conferred by these compounds is mainly through GPX4/NRF2-independent mechanisms. Among them, only ISL could effectively rescue ferroptosis induced by FINO2, which is a stable oxidant of ferrous iron, suggesting that ISL may have the properties of an iron chelator. Consistent with the hypothesis, both computational tools and X-ray photoelectron spectroscopy supported the binding between ISL and iron ions. And ISL greatly inhibited excessive iron-dependent ferroptotic cell death through limiting intracellular iron accumulation. Furthermore, its iron chelator activity also protected mice from organ injury in an acute iron overload model. In conclusion, this study provided valuable insights for developing effective anti-ferroptosis agents from natural products, which represent a potential therapeutic strategy for treating ferroptosis-associated organ damage.