Spinal cord injury (SCI) is a destructive neurological disorder that is characterized by impaired sensory and motor function. Inhibition of bromodomain protein 4 (Brd4) has been shown to promote the maintenance of cell homeostasis by activating autophagy. However, the role of Brd4 inhibition in SCI and the underlying mechanisms are poorly understood. Thus, the goal of the present study was to evaluate the effects of sustained Brd4 inhibition using the bromodomain and extraterminal domain (BET) inhibitor JQ1 on the regulation of apoptosis, oxidative stress and autophagy in a mouse model of SCI. First, we observed that Brd4 expression at the lesion sites of mouse spinal cords increased after SCI. Treatment with JQ1 significantly decreased the expression of Brd4 and improved functional recovery for up to 28 day after SCI. In addition, JQ1-mediated inhibition of Brd4 reduced oxidative stress and inhibited the expression of apoptotic proteins to promote neural survival. Our results also revealed that JQ1 treatment activated autophagy and restored autophagic flux, while the positive effects of JQ1 were abrogated by autophagy inhibitor 3-MA intervention, indicating that autophagy plays a crucial role in therapeutic effects Brd4 induced by inhibition of the functional recovery SCI. In the mechanistic analysis, we observed that modulation of the AMPK-mTOR-ULK1 pathway is involved in the activation of autophagy mediated by Brd4 inhibition. Taken together, the results of our investigation provides compelling evidence that Brd4 inhibition by JQ1 promotes functional recovery after SCI and that Brd4 may serve as a potential target for SCI treatment.

脊髓损伤（SCI）是一种破坏性神经系统疾病，其特征是感觉和运动功能受损。溴结构域蛋白4（Brd4）的抑制作用已显示可通过激活自噬促进细胞稳态的维持。但是，人们尚不清楚Brd4抑制在SCI中的作用及其潜在机制。因此，本研究的目的是评估在SCI小鼠模型中使用溴结构域和末端外域（BET）抑制剂JQ1对Brd4的持续抑制作用对细胞凋亡，氧化应激和自噬的调节作用。首先，我们观察到SCI后在小鼠脊髓病变部位的Brd4表达增加。在脊髓损伤后长达28天，用JQ1处理可显着降低Brd4的表达并改善功能恢复。此外，JQ1介导的对Brd4的抑制作用降低了氧化应激并抑制了凋亡蛋白的表达，从而促进了神经的存活。我们的结果还显示，JQ1治疗激活自噬并恢复自噬通量，而JQ1的积极作用被自噬抑制剂3-MA干预所废止，表明自噬在抑制功能恢复SCI诱导的Brd4的治疗作用中起着关键作用。在机理分析中，我们观察到AMPK-mTOR-ULK1途径的调节与Brd4抑制介导的自噬的激活有关。综上所述，我们的研究结果提供了令人信服的证据，表明JQ1对Brd4的抑制促进了SCI后的功能恢复，并且Brd4可能成为SCI治疗的潜在靶标。