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含溴结构域蛋白4的敲低促进蛛网膜下腔出血小鼠模型中的神经元铁死亡。

Bromodomain-containing protein 4 knockdown promotes neuronal ferroptosis in a mouse model of subarachnoid hemorrhage.

作者信息

Lu Peng, Zhang Fan, Yang Lei, He Yijing, Kong Xi, Guo Kecheng, Xie Yuke, Xie Huangfan, Xie Bingqing, Jiang Yong, Peng Jianhua

机构信息

Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China.

Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China.

出版信息

Neural Regen Res. 2026 Feb 1;21(2):715-729. doi: 10.4103/NRR.NRR-D-24-00147. Epub 2024 Jul 29.

DOI:10.4103/NRR.NRR-D-24-00147
PMID:39104173
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12220699/
Abstract

JOURNAL/nrgr/04.03/01300535-202602000-00041/figure1/v/2025-05-05T160104Z/r/image-tiff Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage. Neuronal ferroptosis in particular plays an important role in early brain injury. Bromodomain-containing protein 4, a member of the bromo and extraterminal domain family of proteins, participated in multiple cell death pathways, but the mechanisms by which it regulates ferroptosis remain unclear. The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro . Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons, and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo . In addition, ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage. Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis. Using cleavage under targets and tagmentation analysis, we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro . Furthermore, treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074, a Raf-1 inhibitor, exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway. Moreover, targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage. Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage, and that inhibiting ferroptosis could help treat subarachnoid hemorrhage.

摘要

《期刊》/nrgr/04.03/01300535 - 202602000 - 00041/图1/v/2025 - 05 - 05T160104Z/图像 - tiff 神经元细胞死亡是多种病理生理过程的常见结果，也是蛛网膜下腔出血后神经功能障碍的关键因素。特别是神经元铁死亡在早期脑损伤中起重要作用。含溴结构域蛋白4是溴结构域和额外末端结构域蛋白家族的成员，参与多种细胞死亡途径，但其调节铁死亡的机制尚不清楚。本研究的主要目的是探讨含溴结构域蛋白4在体内和体外对蛛网膜下腔出血后神经元铁死亡的影响。我们的研究结果显示，内源性含溴结构域蛋白4与神经元共定位，在体内大脑皮质蛛网膜下腔出血48小时后其表达降低。此外，蛛网膜下腔出血后体内和体外铁死亡相关途径均被激活。对神经元中含溴结构域蛋白4进行靶向抑制，通过铁蛋白自噬增加脂质过氧化和细胞内亚铁积累，最终导致神经元铁死亡。使用靶向切割和标签化分析，我们发现体外氧合血红蛋白刺激后，含溴结构域蛋白4在Raf - 1启动子区域的富集减少。此外，用Raf - 1抑制剂GW5074处理含溴结构域蛋白4敲低的HT - 22细胞系，通过抑制Raf - 1/ERK1/2信号通路加剧了神经元铁死亡。而且，对神经元含溴结构域蛋白4进行靶向抑制会加剧蛛网膜下腔出血后的早期和长期神经功能缺损。我们的研究结果表明，含溴结构域蛋白4在蛛网膜下腔出血后可能具有神经保护作用，抑制铁死亡可能有助于治疗蛛网膜下腔出血。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4843/12220699/0b2496de3da1/NRR-21-715-g011.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4843/12220699/e29735f13893/NRR-21-715-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4843/12220699/dad58bc1fa14/NRR-21-715-g009.jpg
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