CXCL14 drives age-related intervertebral disc degeneration via NF-κB pathway activation in a multiomic study

Intervertebral disc degeneration (IDD), a common cause of chronic low back pain, strongly impacts daily life. Although previous studies have identified certain biomarkers indicating IDD, comprehensive analyses that integrate transcriptomic and proteomic data to elucidate age-related changes in IDD are lacking. We addressed this issue by integrating transcriptomic and proteomic analyses to identify key molecular signatures that may be potential therapeutic targets for improving the treatment of age-related IDD. We used transcriptomic and proteomic analyses to identify key regulatory genes associated with IDD. We performed RNA sequencing and mass spectrometry of 3 elderly patients with IDD and 3 younger patients with intervertebral disc lesions. Statistical analysis and GO and KEGG enrichment analyses were employed to interpret the transcriptomic and proteomic data. Validation was performed with external datasets and RT‒qPCR. Gene regulatory network and ceRNA network analyses revealed the factors associated with characteristic genes. Transcriptomic and proteomic analyses revealed 45 differentially expressed genes (DEGs) and 34 differentially expressed proteins (DEPs) associated with IDD. We identified CXCL14 as the sole molecule significantly upregulated in IDD at both the transcriptome (4.2-fold, p < 0.001) and proteome levels (3.8-fold, p = 0.003). RT‒qPCR confirmed CXCL14 overexpression in elderly IDD patients (|log2-fold change| =4.1, p < 0.001), consistent with external dataset analysis (GSE147383: |log2-fold change| =1.3, p = 0.008). Gene regulatory networks revealed that CXCL14 interacts with inflammatory mediators (IL-1β and TNF-α) and activates the NF-κB pathway, a key driver of extracellular matrix degradation and inflammation. ceRNA network analysis further identified hsa-miR-582-3p and hsa-miR-150-5p as potential upstream regulators of CXCL14. We analysed the expression profiles of elderly IDD patients and younger patients through transcriptomic and proteomic analyses, identifying unique molecular features associated with IDD. These findings lay a foundation for developing targeted treatments for elderly IDD patients and provide broader insights into potential therapeutic strategies for managing ageing-related IDD across different patient populations. CXCL14 is a potential therapeutic target for pain associated with age-related IDD and could inform the development of novel drug therapies and diagnostic tools, potentially improving clinical outcomes and providing a basis for personalized treatment approaches in managing chronic low back pain and IDD.