Ferroptosis is implicated in diverse human diseases. Ferroptosis inducers hold great potential for cancer therapy. The existing ferroptosis inducers, however, lack structural diversity, and only a few of them are suitable for in vivo applications. Herein, by phenotypic screenings, we discovered a new ferroptosis inducer FA-S, a 2-(trifluoromethyl)benzimidazole derivative, from which a series of its analogues were designed and synthesized to improve the activity. This produced the most potent compound FA16 with single-digit micromolar activity of ferroptosis induction and satisfactory metabolic stability. Further studies demonstrated that FA16 induced ferroptosis by inhibiting cystine/glutamate antiporter (system X_c⁻). It is noteworthy that analogue FA16 has more favorable metabolic stability than the classic system X_c⁻ inhibitor erastin, which is not suitable for in vivo studies. FA16 significantly inhibited tumor growth in the HepG2 xenograft model by inducing ferroptosis. This work provides new ferroptosis inducers with a novel scaffold, but also a promising lead for hepatocellular carcinoma treatment. Our work reveals a suitable in vivo ferroptosis-inducing tool to explore the mechanisms underlying ferroptosis and the relevance of ferroptosis to pathogenesis of human diseases.

铁死亡与多种人类疾病有关。铁死亡诱导剂在癌症治疗方面具有巨大潜力。然而，现有的铁死亡诱导剂缺乏结构多样性，只有少数适​​合体内应用。在此，通过表型筛选，我们发现了一种新的铁死亡诱导剂FA-S，一种 2-(三氟甲基)苯并咪唑衍生物，并设计合成了一系列类似物以提高其活性。这产生了最有效的化合物FA16，具有单位数微摩尔的铁死亡诱导活性和令人满意的代谢稳定性。进一步的研究表明，FA16通过抑制胱氨酸/谷氨酸逆向转运蛋白 (system X _c⁻ ). 值得注意的是，类似物FA16具有比经典系统 X _c ^-抑制剂 erastin 更有利的代谢稳定性，后者不适用于体内研究。FA16通过诱导铁死亡显着抑制 HepG2 异种移植模型中的肿瘤生长。这项工作为新的铁死亡诱导剂提供了一个新的支架，同时也为肝细胞癌的治疗提供了一个有前途的线索。我们的工作揭示了一种合适的体内铁死亡诱导工具，以探索铁死亡的潜在机制以及铁死亡与人类疾病发病机制的相关性。