Shun Li, Na Qiu, Chao Zhou, Andrew Ni, Ping Sun, Jiajun Liu, Xin‐Lei Huang, Tianqing Xiong, Yuchi Zhang, Haizhou Liu, Xiaotao Xu, Rui Wang, Shiqing Zhang, Yu‐Xin Zhang, Silvia Liu, C. Edward Dixon, Jun Chen, Ke‐Jie Yin
Traumatic brain injury (TBI) disrupts the blood-brain barrier (BBB) and compromises endothelial function, leading to persistent neurological dysfunction. Although miR-15a/16-1 deletion has recently been shown to be neuroprotective in brain injury, the endothelial pathways mediating long-term structural and functional recovery after TBI remain unknown. Here, we demonstrate endothelial cell-specific deletion of miR-15a/16-1 is sufficient to confer neurorestoration after TBI by reducing acute BBB leakage, preserving white and gray matter integrity, and accelerating sensorimotor and cognitive recovery. Mechanistically, transcriptomic profiling identified SYNE1 as a direct downstream target of miR-15a/16-1, validated via in-silico binding prediction and 3'-UTR luciferase assays. Crucially, endothelial cell-targeted AAV-mediated knockdown of SYNE1 abrogated the neurorestorative effects of miR-15a/16-1 deletion, indicating SYNE1 is required for its function. Furthermore, single-cell RNA-seq analysis of human TBI tissue demonstrates significant downregulation of SYNE1 in endothelial cells within the contusion core relative to pericontusional endothelium. Together, these findings define a previously unrecognized miR-15a/16-1-SYNE1 axis that promotes endothelial repair after TBI, with significant translational potential.