Abstract：
Intervertebral disc degeneration (IDD) is a highly prevalent musculoskeletal disorder that is associated with considerable morbidity. However, there is currently no drug available that has a definitive therapeutic effect on IDD. In this study, we aimed to identify the molecular features and potential therapeutic targets of IDD through a comprehensive multiomics profiling approach. By integrating transcriptomics, proteomics, and ultrastructural analyses, we discovered dysfunctions in various organelles, including mitochondria, the endoplasmic reticulum, the Golgi apparatus, and lysosomes. Metabolomics analysis revealed a reduction in total phosphatidylcholine (PC) content in IDD. Through integration of multiple omics techniques with disease phenotypes, a pivotal pathway regulated by the lysophosphatidylcholine acyltransferase 1 (LPCAT1)-PC axis was identified. LPCAT1 exhibited low expression levels and exhibited a positive correlation with PC content in IDD. Suppression of LPCAT1 resulted in inhibition of PC synthesis in nucleus pulposus cells, leading to a notable increase in nucleus pulposus cell senescence and damage to cellular organelles. Consequently, PC exhibits potential as a therapeutic agent, as it facilitates the repair of the biomembrane system and alleviates senescence in nucleus pulposus cells via reversal of downregulation of the LPCAT1-PC axis.
摘要：
椎间盘退变（IDD）是一种非常普遍的肌肉骨骼疾病，与相当高的发病率有关。然而,目前尚无对IDD有明确治疗作用的药物.在这项研究中,我们的目标是通过一个全面的多组学分析方法来确定IDD的分子特征和潜在治疗靶点.通过整合转录组学，蛋白质组学，和超微结构分析，我们发现了各种细胞器的功能障碍，包括线粒体,内质网,高尔基体,和溶酶体.代谢组学分析显示IDD中总磷脂酰胆碱（PC）含量降低。通过整合多种组学技术与疾病表型，确定了由溶血磷脂酰胆碱酰基转移酶1（LPCAT1）-PC轴调节的关键途径。LPCAT1表达水平较低，与IDD中PC含量呈正相关。LPCAT1的抑制导致髓核细胞中PC合成的抑制,导致髓核细胞衰老和细胞器损伤的显着增加。因此,PC显示出作为治疗剂的潜力，因为它促进生物膜系统的修复，并通过逆转LPCAT1-PC轴的下调来减轻髓核细胞的衰老。
