Ferroptosis is an iron-dependent regulated cell death, which has been implicated in the onset and progression of numerous diseases. Ferroptosis inhibitors are thought as potential agents for treating these related diseases. However, the majority of currently available ferroptosis inhibitors are antioxidants or iron chelators (called classical ferroptosis inhibitors), which might have potential risks of side effects during clinical use. Herein, we report the discovery of phenazine derivatives as a new class of non-classical ferroptosis inhibitors. Structure-activity relationship of these series compounds led to the discovery of the most active compound 13l with an EC50 value of 0.0007 μM. Mechanistically, 13l could inhibit NCOA4-mediated ferritinophagy, hence protecting cells from ferroptosis. Notably, in the acetaminophen-induced acute liver injury model, 13l showed an excellent therapeutic effect. Overall, this compound reported here could be a promising lead compound for drug discovery targeting ferroptosis.

中文翻译：

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吩嗪衍生物作为一类新型非经典铁死亡抑制剂的发现及其在小鼠肝损伤模型中的疗效评价


铁死亡是一种铁依赖性调节细胞死亡，与许多疾病的发生和发展有关。铁死亡抑制剂被认为是治疗这些相关疾病的潜在药物。然而，目前可用的大多数铁死亡抑制剂是抗氧化剂或铁螯合剂（称为经典铁死亡抑制剂），它们在临床使用过程中可能存在潜在的副作用风险。在此，我们报道了吩嗪衍生物作为一类新型非经典铁死亡抑制剂的发现。这些系列化合物的构效关系导致发现了最活跃的化合物 13l，EC50 值为 0.0007 μM。从机制上讲，13l 可以抑制 NCOA4 介导的铁蛋白自噬，从而保护细胞免受铁死亡。值得注意的是，在对乙酰氨基酚诱导的急性肝损伤模型中，13l 显示出极好的治疗效果。总体而言，此处报道的这种化合物可能是一种很有前途的先导化合物，用于靶向铁死亡的药物发现。