Revealing the Correlation Between NLRP3 Inflammasome-Related Genes and Intervertebral Disc Degeneration Based Multiomic Analysis and Experimental Validation.

PURPOSE: NLRP3 inflammasome plays a pivotal role in the pathogenesis of intervertebral disc (IVD) degeneration (IDD). This study aimed to identify NLRP3 inflammasome-related biomarkers in IDD and analyze their functions.

METHODS

First, the differentially expressed genes (DEGs) (IDD vs. control) in GSE124272 were detected. The NLRP3 inflammasome-related genes (NIRGs) scores for all samples were calculated using single-sample gene set enrichment analysis (ssGSEA). Subsequently, the key module with the strongest correlation with NIRGs scores was selected using weighted gene coexpression network analysis (WGCNA). Biomarkers were defined as the DEGs and genes showing consistent expression trends across both the GSE124272 and GSE150408 datasets. Function enrichment and immune infiltration were analyzed. The abundance of the key biomarkers was validated by real-time quantitative PCR (RT-qPCR). To explore the effect of core targets on IDD by constructing IDD in vitro model.

RESULTS

About 1608 intersection genes were derived from overlapping the above 2123 DEGs and 10695 key module genes. Subsequently, the top 10 genes were identified. Based on gene expression analysis, disheveled, EGL-10, and pleckstrin domain-containing 1 (DEPDC1), and Opa interacting protein 5 (OIP5) were selected as biomarkers. Functional enrichment analysis revealed that these biomarkers were primarily enriched in cytosolic ribosomes and DNA replication. Immune infiltration analysis identified 13 differential immune cells. Endothelial cells were inversely correlated with DEPDC1, whereas conventional dendritic cells (CDC) demonstrated a pronounced positive relationship with OIP5. RT-qPCR results confirmed that the expression of OIP5 and DEPDC1 in IDD patients was downregulated by more than 50% (p < 0.05). Cell experiments showed that up-regulation of OIP5 led to a 2-fold reduction in cell proliferation (p < 0.001) and a three-fold increase in apoptosis in nucleus pulposus (NP) cells derived from IDD patients (p < 0.001).

CONCLUSION

Taken together, OIP5 has been identified as a peripheral blood biomarker linked to the NLRP3 inflammasome and may be involved in the pathogenesis of IDD.