Low back pain (LBP) is a prevalent clinical condition that imposes substantial economic burdens on society. Intervertebral disc degeneration (IVDD) is recognized as a major contributing factor to LBP. Recent studies have highlighted the pivotal role of microRNAs (miRNAs) in regulating the onset and progression of IVDD. Understanding the involvement of miRNAs in IVDD will expand our knowledge of the underlying mechanisms and potentially identify novel therapeutic targets for managing LBP. However, the pathological process of IVDD and the miRNA-mediated pathomechanism in IVDD remain unclear. Herein, we comprehensively analyzed and divided the pathological process of IVDD into three stages based on the analysis by Risbud and colleagues. Results showed that IVDD was especially associated with cell death, oxidative stress, inflammatory and immune response, and extracellular matrix (ECM) metabolism. Subsequently, we obtained human normal and degenerative nucleus pulposus tissues, which were visually confirmed through histological staining techniques such as HE and TUNEL staining. RNA sequencing was then performed on these tissue samples. Additionally, miRNA (GSE116726) and mRNA (GSE56081/GSE70362/GSE23130/GSE34095) datasets were collected from the GEO database. Our analysis revealed that miR-15a-5p was significantly upregulated IVDD, as validated by both RNA sequencing and qRT-PCR experiments. To further refine our findings, bioinformatics analysis was conducted, merging the targets of miR-15a-5p and multiple mRNA datasets, ultimately identifying the overlapping IVDD-associated mRNAs. Notably, many cuproptosis-related genes (CRGs), ferroptosis-related genes, oxidative stress-related genes, and immunity-related genes were potential targets of miR-15a-5p. The miR-15a-5p-mRNA network was constructed using Cytoscape software. Additionally, PPI, functional, and pathway enrichment analyses of the CRGs were also performed. We found that MTF1, one of the CRGs, was highly expressed in IVDD and primarily localized in the nucleus of nucleus pulposus cells. These findings suggest that miR-15a-5p is a potential biomarker in IVDD, and targeting the miR-15a-5p-mRNA signaling pathway may be a promising strategy for treating IVDD diseases.Copyright © 2023. Published by Elsevier B.V.