Ferroptosis is a form of iron-dependent regulated cell death. Evidence of its existence and the effects of its inhibitors on subarachnoid hemorrhage (SAH) is still lacking. In the present study, we found that liproxstatin-1 protected HT22 cells against hemin-induced injury by protecting mitochondrial functions and ameliorating lipid peroxidation. In in vivo experiments, we demonstrated the presence of characteristic shrunken mitochondria in ipsilateral cortical neurons after SAH. Moreover, liproxstatin-1 attenuated the neurological deficits and brain edema, reduced neuronal cell death, and restored the redox equilibrium after SAH. The inhibition of ferroptosis by liproxstatin-1 was associated with the preservation of glutathione peroxidase 4 and the downregulation of acyl-CoA synthetase long-chain family member 4 as well as cyclooxygenase 2. In addition, liproxstatin-1 decreased the activation of microglia and the release of IL-6, IL-1β, and TNF-α. These data enhance our understanding of cell death after SAH and shed light on future preclinical studies.

铁死亡是一种铁依赖性调节细胞死亡形式。仍然缺乏关于其存在及其抑制剂对蛛网膜下腔出血 (SAH) 影响的证据。在本研究中，我们发现 liproxstatin-1 通过保护线粒体功能和改善脂质过氧化来保护 HT22 细胞免受血红素诱导的损伤。在体内实验中，我们证明了 SAH 后同侧皮质神经元中存在特征性的收缩线粒体。此外，liproxstatin-1 可减轻神经功能缺损和脑水肿，减少神经元细胞死亡，并恢复 SAH 后的氧化还原平衡。liproxstatin-1 对铁死亡的抑制与谷胱甘肽过氧化物酶 4 的保留和酰基辅酶 A 合成酶长链家族成员 4 以及环氧合酶 2 的下调有关。此外，liproxstatin-1 降低了小胶质细胞的活化和IL-6、IL-1β 和 TNF-α 的释放。这些数据增强了我们对 SAH 后细胞死亡的理解，并为未来的临床前研究提供了启示。