Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (2): 715-729.doi: 10.4103/NRR.NRR-D-24-00147

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

Peng Lu1, 2, #, Fan Zhang1, 2, #, Lei Yang1, 2, Yijing He2, 3, Xi Kong2, 4, Kecheng Guo1, 2, 3, Yuke Xie1, 2, 3, Huangfan Xie2, 4, Bingqing Xie2, 4, Yong Jiang1, 2, 3, 4, *, Jianhua Peng1, 2, 5, *   

  1. 1 Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China;  2 Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China;  3 Sichuan Clinical Research Center for Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China;  4 Institute of Brain Science, Southwest Medical University, Luzhou, Sichuan Province, China;  5 Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
  • Online:2026-02-15 Published:2025-05-24
  • Contact: Jianhua Peng, MD, pengjianhua@swmu.edu.cn; Yong Jiang, MD, PhD, jiangyong@swmu.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 82371310 (to YJ), 82271306 (to JP); the Sichuan Science and Technology Support Program, Nos. 2023YFH0069 (to JP), 2023NSFSC0028 (to YJ), 2023NSFSC1559 (to YJ), 2022YFS0615 (to JP), 2022NSFSC1421 (to JP); Scientific Research Project of Sichuan Provincial Health Commission, No. 23LCYJ040 (to YJ); and Youth Foundation of Southwestern Medical University and Southwest Medical University Project, Nos. 2020ZRQNA038 (to JP), 2021ZKZD013 (to JP), 2021LZXNYD-P01 (to YJ), 2023QN014 (to JP).

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Abstract: 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.

Key words: bromodomain-containing protein 4, cell death, early brain injury, ferritinophagy, ferroptosis, neurological deficits, neuron, oxidative stress, RAF proto-oncogene serine/threonine-protein kinase (Raf-1), subarachnoid hemorrhage