Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Exp Neurol. 2023 Jan;359:114269. doi: 10.1016/j.expneurol.2022.114269. Epub 2022 Nov 5.
Stroke patients are often complicated by cerebral ischemia-reperfusion injury (CIRI) after the restoration of cerebral perfusion, and how to prevent CIRI at an early stage has received close attention. The imbalance of iron metabolism is one of the essential factors in the aggravation of CIRI, and NCOA4-mediated ferritinophagy, as a critical pathway to regulate iron metabolism, is expected to be an effective intervention target. We established a mouse model of cerebral ischemia-reperfusion (CIR) with NCOA4 silencing. We found that activation of NCOA4-mediated ferritinophagy atthe early stage of CIR mediated the onset of oxidative stress and contributed to autophagy and apoptosis, and eventually resulted in increased brain injury. This suggests that NCOA4-mediated ferritinophagy plays a vital role in early CIR and can be an effective target to prevent and treat CIRI. We next explored the upstream regulatory targets of NCOA4-mediated ferritinophagy. The previous evidence for the cGAS-STING pathway's importance during CIR and its strong relationship with autophagy attracted our attention. To investigate whether the cGAS-STING pathway regulates NCOA4-mediated ferritinophagy, we further administered a cGAS inhibitor to mice with CIR and overexpressed NCOA4. Along with the inhibition of the cGAS-STING pathway, ferritinophagy, oxidative stress, autophagy, and apoptosis were inhibited, and CIRI was ameliorated, which was attenuated by NCOA4 overexpression. In conclusion, our results suggest that activation of the cGAS-STING pathway exacerbates CIRI at the early stage of CIR, which may be achieved by mediating NCOA4-mediated ferritinophagy.
中风患者在脑灌注恢复后常常并发脑缺血再灌注损伤（CIRI），如何在早期预防 CIRI 受到密切关注。铁代谢失衡是 CIRI 加重的重要因素之一，NCOA4 介导的铁蛋白自噬作为调节铁代谢的关键途径，有望成为有效的干预靶点。我们建立了 NCOA4 沉默的脑缺血再灌注（CIR）小鼠模型。我们发现，CIR 早期激活 NCOA4 介导的铁蛋白自噬介导氧化应激的发生，并促进自噬和细胞凋亡，最终导致脑损伤增加。这表明 NCOA4 介导的铁蛋白自噬在早期 CIR 中起重要作用，可作为预防和治疗 CIRI 的有效靶点。接下来，我们探讨了 NCOA4 介导的铁蛋白自噬的上游调控靶点。先前的证据表明，cGAS-STING 通路在 CIR 期间的重要性及其与自噬的强烈关系引起了我们的关注。为了研究 cGAS-STING 通路是否调节 NCOA4 介导的铁蛋白自噬，我们进一步用 cGAS 抑制剂处理 CIR 小鼠，并过表达 NCOA4。随着 cGAS-STING 通路的抑制，铁蛋白自噬、氧化应激、自噬和细胞凋亡被抑制，CIRI 得到改善，而过表达 NCOA4 则减弱了这种改善。总之，我们的结果表明，cGAS-STING 通路的激活在 CIR 的早期阶段加重 CIRI，这可能是通过介导 NCOA4 介导的铁蛋白自噬来实现的。
