PDF(Pubmed)
Abstract：
Intervertebral disc degeneration (IVDD) severely affects the work and the quality of life of people. We previously demonstrated that silencing activation transcription factor 3 (ATF3) blocked the IVDD pathological process by regulating nucleus pulposus cell (NPC) ferroptosis, apoptosis, inflammation, and extracellular matrix (ECM) metabolism. Nevertheless, whether miR-874-3p mediated the IVDD pathological process by targeting ATF3 remains unclear. We performed single-cell RNA sequencing (scRNA-seq) and bioinformatics analysis to identify ATF3 as a key ferroptosis gene in IVDD. Then, Western blotting, flow cytometry, ELISA, and animal experiments were performed to validate the roles and regulatory mechanisms of miR-874-3p/ATF3 signalling axis in IVDD. ATF3 was highly expressed in IVDD patients and multiple cell types of IVDD rat, as revealed by scRNA-seq and bioinformatics analysis. GO analysis unveiled the involvement of ATF3 in regulating cell apoptosis and ECM metabolism. Furthermore, we verified that miR-874-3p might protect against IVDD by inhibiting NPC ferroptosis, apoptosis, ECM degradation, and inflammatory response by targeting ATF3. In vivo experiments displayed the protective effect of miR-874-3p/ATF3 axis on IVDD. These findings propose the potential of miR-874-3p and ATF3 as biomarkers of IVDD and suggest that targeting the miR-874-3p/ATF3 axis may be a therapeutic target for IVDD.
摘要：
椎间盘退变(IVDD)严重影响人们的工作和生活质量。我们先前证明沉默激活转录因子3（ATF3）通过调节髓核细胞（NPC）的铁凋亡来阻断IVDD的病理过程，凋亡，炎症,和细胞外基质（ECM）代谢。然而，miR-874-3p是否通过靶向ATF3介导IVDD病理过程尚不清楚.我们进行了单细胞RNA测序（scRNA-seq）和生物信息学分析，以确定ATF3是IVDD中的关键铁性凋亡基因。然后，西方印迹,流式细胞术,ELISA,和动物实验验证miR-874-3p/ATF3信号轴在IVDD中的作用和调控机制。ATF3在IVDD患者和多种细胞类型的IVDD大鼠中高表达，正如scRNA-seq和生物信息学分析所揭示的那样。GO分析揭示了ATF3参与调节细胞凋亡和ECM代谢。此外，我们验证了miR-874-3p可能通过抑制NPC铁性凋亡来抵抗IVDD，凋亡，ECM降解，和靶向ATF3的炎症反应。体内实验显示miR-874-3p/ATF3轴对IVDD的保护作用。这些发现提出了miR-874-3p和ATF3作为IVDD生物标志物的潜力，并表明靶向miR-874-3p/ATF3轴可能是IVDD的治疗靶标。
