Fatty Acid-binding Protein 4 Exacerbates Blood–brain Barrier Disruption Through the JNK/c-Jun/MMP12 Pathway After Traumatic Brain Injury

Elevated circulating levels of fatty acid-binding protein 4 (FABP4) correlate with poor prognosis in brain injury patients. However, the molecular mechanisms by which FABP4 regulates blood-brain barrier (BBB) disruption after traumatic brain injury (TBI) remain unclear. This study investigates the molecular mechanisms by which FABP4 regulates BBB disruption following TBI and evaluates the therapeutic potential of the selective FABP4 inhibitor BMS309403 in TBI pathology. Western blot and immunofluorescence were used to detect FABP4 expression in TBI mouse brain tissue and BV2 cells. Fabp4 knockout mice were generated, and MRI, TUNEL staining, brain water content measurement, and Evans blue staining were performed to assess BBB disruption and neuronal apoptosis. Behavioral experiments were conducted to evaluate neurological deficits. The effect of microglial cells on endothelial cell tight junctions was assessed using Transwell assays. Transcriptome sequencing identified potential downstream mechanisms, and ChIP-qPCR validated P-c-Jun binding to the MMP12 promoter region. The therapeutic potential of BMS309403 was also assessed. FABP4 expression was significantly increased in TBI mice and LPS-stimulated BV2 cells. Genetic deletion of FABP4 alleviated TBI pathology, as evidenced by reduced lesion volume, cerebral edema, neuronal apoptosis, and neurological deficits. BBB disruption was attenuated with reduced degradation of tight junction proteins. Mechanistically, FABP4 promotes the degradation of tight junction proteins and increases BBB permeability by regulating MMP12 expression. FABP4 activates JNK, facilitating the binding of P-c-Jun to the Mmp12 promoter. BMS309403 effectively preserved BBB integrity, reduced cerebral edema, and improved neurological outcomes in TBI mouse models. Finally, preclinical research revealed a correlation between the plasma FABP4 level and the neurological outcome in TBI patients. FABP4 exacerbates BBB disruption after TBI via the JNK/c-Jun/MMP12 pathway. Inhibition of FABP4 offers a potential therapeutic strategy for improving TBI outcomes.