Background: Acute gouty arthritis is a common inflammatory arthropathy resulting from urate deposition in joints during persistent hyperuricemia. Nevertheless, effective therapeutic strategies are still unavailable. Here, we propose the crucial role of bromodomain-containing protein 4 (BRD4) in acute gouty arthritis./nMethods: Therapeutic effect of BRD4 specific inhibitor JQ-1 on acute gouty arthritis was evaluated in vivo and in vitro. Pyroptosis was analyzed by Caspase-1/PI double staining and cleavage of gasdermin D (GSDMD). Expression of key factors involved in BRD4/NF-κB/NLRP3/GSDMD signaling pathway were measured by western blot, and colocalization of NLRP3 and ASC was detected using immunofluorescence. In addition, the role of BRD4 on monosodium uric acid crystals (MSU)-induced pyroptosis was verified in BRD4 siRNA-transfected THP-1 cells./nResults: Pretreatment of JQ1 and BRD4 siRNA significantly suppressed pyroptosis and inhibited activation of p65 NF-κB signaling as well as NLRP3 inflammasome in THP-1 cells exposed to MSU. In vivo, JQ-1 administration could effectively attenuate joint swelling and synovial inflammation in rats treated by intra-articular injection of MSU. More importantly, MSU led to macrophage pyroptosis and Brd4/NF-κB/NLRP3/GSDMD signaling induction in rat synoviums, which was improved by JQ-1./nConclusions: Our study identifies the role of BRD4 in MSU-induced pyroptosis through regulating NF-κB/NLRP3/GSDMD signaling pathways, which provides a potential target for treatment of acute gouty arthritis.

中文翻译：

---

靶向BRD4通过调节细胞焦亡预防急性痛风性关节炎

背景：急性痛风性关节炎是一种常见的炎症性关节病，由持续性高尿酸血症期间尿酸沉积在关节中引起。尽管如此，仍然没有有效的治疗策略。在这里，我们提出了含溴结构域蛋白 4（BRD4）在急性痛风性关节炎中的关键作用。/n方法：在体内和体外评估了 BRD4 特异性抑制剂 JQ-1 对急性痛风性关节炎的治疗效果。通过 Caspase-1/PI 双染色和 Gasdermin D (GSDMD) 裂解分析细胞焦亡。Western blot检测BRD4/NF-κB/NLRP3/GSDMD信号通路关键因子的表达，免疫荧光检测NLRP3与ASC的共定位。此外，在 BRD4 siRNA 转染的 THP-1 细胞中验证了 BRD4 对尿酸单钠晶体 (MSU) 诱导的细胞焦亡的作用。/n结果：JQ1 和 BRD4 siRNA 的预处理显着抑制了细胞焦亡并抑制了暴露于 MSU 的 THP-1 细胞中 p65 NF-κB 信号传导以及 NLRP3 炎性体的激活。在体内，JQ-1 给药可有效减轻 MSU 关节内注射治疗大鼠的关节肿胀和滑膜炎症。更重要的是，MSU 导致大鼠滑膜中巨噬细胞焦亡和 Brd4/NF-κB/NLRP3/GSDMD 信号诱导，而 JQ-1./n 改善了这一点结论：我们的研究确定了 BRD4 通过调节 MSU 诱导的焦亡NF-κB/NLRP3/GSDMD 信号通路，为治疗急性痛风性关节炎提供了潜在的靶点。