Background: Intracerebral hemorrhage (ICH) is a subtype of stroke causing severe neuronal injury and functional deficits. This study aims to investigate the impact of bromodomain-containing protein 4 (BRD4) on ICH progression and the therapeutic efficacy of the bromodomain and extraterminal (BET) inhibitor JQ1.

Methods: An ICH rat model was established by injecting autologous blood into the basal ganglia. During treatment, the rats received either JQ1 (50 mg/kg) or vehicle. Neurological and motor outcomes were measured via the foot-fault test, modified neurological severity score, and rotarod performance test. Cognitive function of the experimental rats was tested with the Morris water maze. Brain edema of the animals was evaluated using the wet–dry weight method, coupled with some histopathologic assessments by hematoxylin–eosin (H&E) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were employed to analyze neuronal apoptosis. Expression of proteins related to apoptosis, autophagy, and the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathway were evaluated using Western blotting.

Results: BRD4 expression was notably increased in the cerebral tissue of ICH rats (p < 0.01), while the administration of JQ1 decreased the levels of BRD4 in rats with ICH (p < 0.01). The administration of JQ1 resulted in a reduction in the modified neurological severity score of ICH, a decrease in the misstep frequency of the left forelimb, and a longer time to slip (p < 0.01). Furthermore, relative to the ICH group, rats in the ICH + JQ1 group exhibited a reduction in escape latency, as well as increased platform crossings and longer durations in the target area (p < 0.05). Also, JQ1 reduced the water content, tissue damage, and apoptosis levels in the cerebral tissue affected by ICH (p < 0.01). The JQ1-induced reduction in BRD4 expression inhibited apoptosis-linked protein expression and promoted autophagy-associated protein expression (p < 0.01). Furthermore, JQ1 treatment elevated the p-AMPK/AMPK ratio and suppressed p-mTOR/mTOR levels (p < 0.01).

Conclusion: JQ1 holds the promise in alleviating ICH-induced brain injury by inhibiting BRD4 and modulating the AMPK/mTOR pathway.