Transcriptome data combined with two-sample Mendelian randomization reveal IRF1 and PRKD1 as UPR-related key regulators in intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) is a leading cause of chronic low back pain, yet the molecular mechanisms driving its progression remain incompletely defined. Emerging evidence suggests that endoplasmic reticulum stress and the unfolded protein response (UPR) may play critical roles in disc cell dysfunction. Transcriptomic datasets (GSE70362 and GSE56081) from human nucleus pulposus tissues were integrated to identify UPR-related differentially expressed genes. Functional enrichment, gene set enrichment analysis, and gene set variation analysis analyses were performed to explore associated biological pathways. Protein-protein interaction networks, transcription factor-target predictions, and immune infiltration analyses were conducted. Two-sample Mendelian randomization was applied to assess potential causal relationships between UPR-related genes and IDD. Key genes were further validated using independent datasets and single-cell RNA sequencing data. A total of 26 UPR-related differentially expressed genes were identified, and protein-protein interaction network analysis with hub gene screening highlighted IRF1, PRKD1, CCND1, and PDLIM1 as central regulators. Two-sample Mendelian randomization confirmed the causal associations of IRF1 and PRKD1 with IDD risk. Immune infiltration analysis revealed significant correlations between UPR-related genes and the activity of macrophages and T cells. Single-cell RNA sequencing further validated the differential expression and cell-type specificity of IRF1 and PRKD1 in degenerated nucleus pulposus tissues. This integrative multi-omics and Mendelian randomization study identifies IRF1 and PRKD1 as UPR-related drivers of IDD. These findings provide potential biomarkers and therapeutic targets for IDD management.