Sui Haijing, Sun Zhenyu, Liu Chang, Xi Hongjie
Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Heilongjiang Province Key Laboratory of Research on Anesthesiology and Critical Care Medicine, Harbin, 150001, China.
Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, 150001, China.
Neurochem Int. 2025 Feb;183:105920. doi: 10.1016/j.neuint.2024.105920. Epub 2024 Dec 26.
Cerebral ischemia-reperfusion injury (CIRI) is a common and serious complication of reperfusion therapy in patients with ischemic stroke (IS). The regulation of microglia-mediated neuroinflammation to control CIRI has garnered considerable attention. The balance of iron metabolism is key to maintaining the physiological functions of microglia. Nuclear Receptor Coactivator 4 (NCOA4)-mediated ferritinophagy, an important pathway in regulating iron metabolism, is a promising intervention target. However, studies on the impacts of ferritinophagy on microglia-mediated neuroinflammation are lacking. This study aimed to identify potential treatments for CIRI-induced neuroinflammation by focusing on ferritinophagy and the specific mechanisms whereby iron metabolism regulates microglia-mediated neuroinflammation. CIRI induced the activation of ferritinophagy in microglia, characterized by the upregulation of NCOA4, downregulation of Ferritin Heavy Chain 1 (FTH1), and increased intracellular iron levels. This activation contributes to increased ferroptosis, oxidative stress, and the release of inflammatory factors. Silencing NCOA4 or application of the ferroptosis-specific inhibitor Ferrostatin-1 (Fer-1) effectively suppressed the CIRI-induced damage in vivo and in vitro. While Fer-1 addition did not inhibit the CIRI-activated ferritinophagy, it did partially reverse the alleviation of NCOA4 depletion-induced neuroinflammation, suggesting that ferroptosis is an essential intermediate step in ferritinophagy-induced neuroinflammatory damage. Furthermore, using IS-related transcriptomic data, the cGAS-STING pathway was identified as a crucial mechanism connecting ferritinophagy and ferroptosis. Specific inhibition of the cGAS-STING pathway reduced ferritinophagy-induced ferroptosis and neuroinflammation. In summary, our results indicated that ferritinophagy activates the cGAS-STING signaling pathway, which promotes the inflammatory response and oxidative stress in microglia in a ferroptosis-dependent manner, thereby exacerbating CIRI-induced neuroinflammation. These findings provide theoretical support for the clinical treatment of CIRI.
脑缺血再灌注损伤（CIRI）是缺血性卒中（IS）患者再灌注治疗常见且严重的并发症。小胶质细胞介导的神经炎症调节对于控制CIRI已引起广泛关注。铁代谢平衡是维持小胶质细胞生理功能的关键。核受体辅激活因子4（NCOA4）介导的铁蛋白自噬是调节铁代谢的重要途径，是一个有前景的干预靶点。然而，关于铁蛋白自噬对小胶质细胞介导的神经炎症影响的研究尚缺乏。本研究旨在通过关注铁蛋白自噬以及铁代谢调节小胶质细胞介导的神经炎症的具体机制，确定CIRI诱导的神经炎症的潜在治疗方法。CIRI诱导小胶质细胞中铁蛋白自噬的激活，其特征为NCOA4上调、铁蛋白重链1（FTH1）下调以及细胞内铁水平升高。这种激活导致铁死亡增加、氧化应激以及炎症因子释放。沉默NCOA4或应用铁死亡特异性抑制剂铁抑素-1（Fer-1）可有效抑制体内和体外CIRI诱导的损伤。虽然添加Fer-1并未抑制CIRI激活的铁蛋白自噬，但它确实部分逆转了NCOA4缺失诱导的神经炎症减轻，表明铁死亡是铁蛋白自噬诱导的神经炎症损伤中必不可少的中间步骤。此外，利用与IS相关的转录组数据，cGAS-STING通路被确定为连接铁蛋白自噬和铁死亡的关键机制。特异性抑制cGAS-STING通路可减少铁蛋白自噬诱导的铁死亡和神经炎症。总之，我们的结果表明铁蛋白自噬激活cGAS-STING信号通路，以铁死亡依赖的方式促进小胶质细胞中的炎症反应和氧化应激，从而加剧CIRI诱导的神经炎症。这些发现为CIRI的临床治疗提供了理论支持。
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