GPR124 Alleviates Blood–Brain Barrier Disruption by Enhancing Microvascular Endothelial Function after Traumatic Brain Injury

ABSTRACT Traumatic brain injury (TBI) is a leading cause of death among young adults worldwide. However, the role of G protein‐coupled receptor 124 (GPR124), a key regulator of the nervous system, in TBI remains unexplored. We employed a controlled cortical impact (CCI) model combined with single‐cell RNA sequencing to analyze the localization of GPR124 expression following TBI. Additionally, we used mice with endothelial cell (EC)‐specific conditional knockout (CKO) of GPR124 to perform behavioral experiments. A stretch injury (SI) model was also established to investigate the effects of GPR124 on ECs. Neurological recovery after TBI was significantly impaired in mice with the EC‐specific CKO of GPR124. Furthermore, GPR124 knockdown reduced EC function after SI. Notably, tight junction integrity was disrupted both in vivo and in vitro after GPR124 knockdown. Mass spectrometry and immunoprecipitation analyses confirmed that GPR124 interacts with fibroblast growth factor binding protein‐1, thereby activating the Wnt/β‐catenin pathway. Our study demonstrates that GPR124 regulates microvascular endothelial function and maintains blood–brain barrier integrity by activating the Wnt/β‐catenin pathway. This mechanism plays a crucial role in improving TBI prognosis and may represent a potential new therapeutic target.