2. Academic Validation
  3. DEAD-box helicase DDX24 is essential for endothelial mitochondrial function to maintain the blood-brain barrier

DEAD-box helicase DDX24 is essential for endothelial mitochondrial function to maintain the blood-brain barrier

  • Cell Rep. 2025 Oct 28;44(10):116428. doi: 10.1016/j.celrep.2025.116428.
Shuai Li 1,  Yuxuan Liu 1,  Yingying Dong 1,  Yujiao Gong 1,  Simeng He 1,  Jianyu Yuan 1,  Shengfeng Deng 2,  Qianqian Zhang 1,  Lijie Wang 1,  Fei Liu 3,  Qiuyun Tu 4,  Hong Shan 5,  Huanhuan He 6
Affiliations

Affiliations

  • 1 Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China; Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.
  • 2 Department of Geriatrics, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China.
  • 3 Department of Neurosurgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China. Electronic address: liuf235@mail.sysu.edu.cn.
  • 4 Department of Geriatrics, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China. Electronic address: tuqy3@mail.sysu.edu.cn.
  • 5 Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China; Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China; Department of Interventional Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China. Electronic address: shanhong@mail.sysu.edu.cn.
  • 6 Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China; Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China. Electronic address: hehh23@mail.sysu.edu.cn.
PMID: 41105514 DOI: 10.1016/j.celrep.2025.116428
Abstract

The blood-brain barrier (BBB) is essential for brain function, yet its underlying regulatory mechanisms remain elusive. Here, we identify DEAD-box RNA helicase 24 (DDX24) as a regulator of the BBB. Endothelial-specific Ddx24 knockout (Ddx24ECKO) mice exhibit deficits in learning and memory and increased BBB permeability. Furthermore, DDX24 knockdown in human cerebral microvascular endothelial cells (hCMEC/D3) disrupts the barrier function through occludin phosphorylation and mitochondrial dysfunction. Targeting NADPH Oxidase suppresses BBB hyperpermeability and improves learning and memory deficits in Ddx24ECKO mice. Mechanistically, the DDX24 protein binds to PPFIA4 mRNA and enhances its stability. Consistent with the function of DDX24, PPFIA4 knockdown impairs mitochondrial homeostasis and barrier function in hCMEC/D3 cells. Importantly, DDX24 overexpression attenuates Aβ1-42-induced barrier damage. Taken together, our study uncovers a pivotal role for DDX24 in regulating the BBB via mediating mitochondrial function in endothelial cells, providing a potential therapeutic target for treating BBB-related diseases.

Keywords

CP: Neuroscience; DDX24; PPFIA4; blood-brain barrier; brain microvascular endothelial cells; mitochondrial function.

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