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

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 ( Ddx24 ECKO ) 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 Ddx24 ECKO 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 Aβ 1-42 -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.