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.