Intervertebral disc degeneration (IDD) is considered to be the leading cause of low back pain (LBP). The progression of IDD is closely related to the inflammatory microenvironment, which results in extracellular matrix degradation and cell death. One of the proteins, which have been shown to participate in the inflammatory response, is the bromodomain-containing protein 9 (BRD9). This study aimed to investigate the role and mechanism of BRD9 in regulating IDD. The tumor necrosis factor-α (TNF-α) was used to mimic the inflammatory microenvironment in vitro. Western blot, RT-PCR, immunohistochemistry, immunofluorescence, and flow cytometry were used to demonstrate the effect of BRD9 inhibition or knockdown on matrix metabolism and pyroptosis. We found that the expression of BRD9 was upregulated as IDD progressed. BRD9 inhibition or knockdown alleviated TNF-α-induced matrix degradation, reactive oxygen species (ROS) production, and pyroptosis in rat nucleus pulposus cells. Mechanistically, RNA-seq was used to investigate the mechanism of BRD9 in promoting IDD. Further investigation revealed that BRD9 regulated NOX1 expression. Inhibition of NOX1 could abrogate matrix degradation, ROS production, and pyroptosis caused by BRD9 overexpression. In vivo, the radiological and histological evaluation showed that the pharmacological inhibition of BRD9 alleviated IDD development in rat IDD model. Our results indicated that BRD9 could promote IDD via the NOX1/ROS/ NF-κB axis by inducing matrix degradation and pyroptosis. Targeting BRD9 may be a potential therapeutic strategy in treating IDD.

椎间盘退变 (IDD) 被认为是腰痛 (LBP) 的主要原因。IDD的进展与炎症微环境密切相关，炎症微环境导致细胞外基质降解和细胞死亡。已显示参与炎症反应的蛋白质之一是含溴结构域蛋白 9 (BRD9)。本研究旨在探讨 BRD9 在调节 IDD 中的作用和机制。肿瘤坏死因子-α (TNF-α) 用于模拟体外炎症微环境. Western blot、RT-PCR、免疫组织化学、免疫荧光和流式细胞术用于证明 BRD9 抑制或敲低对基质代谢和细胞焦亡的影响。我们发现 BRD9 的表达随着 IDD 的进展而上调。BRD9 抑制或敲低减轻了 TNF-α 诱导的基质降解、活性氧 (ROS) 产生和大鼠髓核细胞焦亡。从机制上讲，RNA-seq 用于研究 BRD9 促进 IDD 的机制。进一步调查显示 BRD9 调节 NOX1 表达。抑制 NOX1 可以消除由 BRD9 过表达引起的基质降解、ROS 产生和细胞焦亡。体内，放射学和组织学评估表明，BRD9 的药理学抑制减轻了大鼠 IDD 模型中的 IDD 发展。我们的结果表明，BRD9 可以通过诱导基质降解和细胞焦亡，通过 NOX1/ROS/NF-κB 轴促进 IDD。靶向 BRD9 可能是治疗 IDD 的潜在治疗策略。