With increasing evidence that ferroptosis is associated with diverse neurological disorders, targeting ferroptosis offers a promising avenue for developing effective pharmaceutical agents for neuroprotection. In this study, we identified ferroptosis inhibitors as neuroprotective agents from US Food and Drug Administration (FDA)-approved drugs. 1176 drugs have been screened against erastin-induced ferroptosis in HT22 cells, resulting in 89 ferroptosis inhibitors. Among them, 26 drugs showed significant activity with EC below10 μM. The most active ferroptosis inhibitor is lumateperone tosylate at nanomolar level. 11 drugs as ferroptosis inhibitors were not reported previously. Further mechanistic studies revealed that their mechanisms of actions involve free radical scavenging, Fe chelation, and 15-lipoxygenase inhibition. Notably, the active properties of some drugs were firstly revealed here. These ferroptosis inhibitors increase the chemical diversity of ferroptosis inhibitors, and offer new therapeutic possibilities for the treatments of related neurological diseases.

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从 FDA 批准的药物中鉴定出 11 种新的铁死亡抑制剂作为神经保护剂

随着越来越多的证据表明铁死亡与多种神经系统疾病相关，针对铁死亡为开发有效的神经保护药物提供了一条有希望的途径。在这项研究中，我们从美国食品和药物管理局 (FDA) 批准的药物中确定了铁死亡抑制剂作为神经保护剂。已经筛选了 1176 种药物来对抗 HT22 细胞中erastin诱导的铁死亡，产生了 89 种铁死亡抑制剂。其中，26种药物表现出显着的活性，EC低于10μM。最活跃的铁死亡抑制剂是纳摩尔水平的甲苯磺酸鲁美特哌隆。 11种药物作为铁死亡抑制剂未曾报道。进一步的机制研究表明，它们的作用机制涉及自由基清除、Fe 螯合和 15-脂氧合酶抑制。值得注意的是，一些药物的活性特性在这里首次被揭示。这些铁死亡抑制剂增加了铁死亡抑制剂的化学多样性，并为相关神经系统疾病的治疗提供了新的治疗可能性。