Deciphering the regulatory mechanism and therapeutic potential of ECM degradation in intervertebral disc degeneration via multi-omics integration

Background: Intervertebral disc degeneration (IVDD) is a major cause of chronic low back pain, characterized not only by extracellular matrix (ECM) degradation but also by a chronic low-grade inflammatory response. The crosstalk between immune microenvironment dysregulation and protease-driven ECM breakdown remains poorly understood, hindering the development of targeted therapies. Methods: for its effects on ECM preservation and inflammation modulation. Results: MMP3 and ADAMTS1 were identified as core genes driving ECM degradation, and their expression was strongly correlated with the abundance of pro-inflammatory immune cells and activation of inflammatory pathways. The model based on these genes effectively distinguished degenerated discs. Single-cell analysis revealed that high-degradation nucleus pulposus cells exhibited enhanced pro-inflammatory intercellular communication and metabolic reprogramming towards a pro-inflammatory state. Molecular docking confirmed high binding affinity of pravastatin sodium to MMP3 and ADAMTS1. Experimental validation demonstrated that pravastatin sodium alleviated IVDD by reducing ECM degradation, suppressing pro-inflammatory cytokine (e.g., IL-1β) expression, and inhibiting apoptosis. Conclusion: Our study delineates a critical network linking ECM degradation to immune microenvironment activation in IVDD, with MMP3 and ADAMTS1 serving as central hubs. Pravastatin sodium emerges as a promising therapeutic agent capable of disrupting this pathogenic network, offering a novel immunomodulatory strategy for slowing disc degeneration.