Identification of Core Senescence-Related Genes and Characterization of Comprehensive Immune Landscape in Intervertebral Disc Degeneration.

Background: Intervertebral disc degeneration (IVDD) is a musculoskeletal degenerative disease closely associated with age and immunoreaction. However, the mechanism of senescence and immune infiltration landscape in IVDD is still unclear. Our study was aimed at investigating the pivotal senescence-related genes (SRGs) and immune cells involved in IVDD. Methods: We downloaded expression profiles by array from the GEO database and obtained 543 human SRGs from the Human Aging Genomic Resources (HAGR). Differentially expressed gene analysis, GO, KEGG, PPI network analysis, etc., were used to identify senescence-related differentially expressed genes (SRDEGs). We then used WGCNA and machine learning algorithms to explore hub genes and validated the reliability of the results in single-cell RNA sequencing (scRNA-seq) and cell models. Results: We identified a core senescence-associated differentially expressed gene, connective tissue growth factor (CTGF). RNA sequencing revealed significantly upregulated CTGF expression in the degenerative group, a finding consistently validated by both scRNA-seq and in vitro models. CTGF demonstrated promising diagnostic value for IVDD in risk prediction and clinical detection (AUC: 0.8361, 95% CI: 0.668-0.9953). Furthermore, we observed endothelial cells, smooth muscle cells, and erythrocytes within disc tissues, suggesting postdegenerative vascular invasion into the nucleus pulposus. Notably, immune cell infiltration, including B cells, T cells, plasma cells, and macrophages, was detected in both mildly and severely degenerated nucleus pulposus tissues, with a significantly higher abundance of immune cells in the mild degenerative group compared to severe cases. Conclusion: CTGF may play a pivotal role in IVDD, advancing our understanding of disease pathogenesis and demonstrating potential as a diagnostic and therapeutic target. Notably, reduced immune cell infiltration in severe IVDD may stem from either activation of intrinsic repair mechanisms or an immune-exhausted state. Investigating dynamic alterations in immune cell populations during IVDD progression could elucidate the critical role of immunity in disease pathogenesis and inform novel strategies for diagnosis and therapeutic intervention.