Current therapeutic strategies for intervertebral disc degeneration (IDD)-related low back pain are limited to symptomatic alleviation. Notochordal cells (NCs), as progenitor cells of the nucleus pulposus (NP), lead us to develop innovative NC-based new therapies for IDD. A total of 40 NP specimens, obtained according to IDD criteria with defined Pfirrmann grades and histological degeneration score, were categorized as either normal (Grade II) or degenerated (Grade IV). An IDD model was established in SD rats by needle puncture of the annulus fibrosus. Degenerated NP tissue was identified using MRI, H&E, Safranin O, and Masson staining. NCs and NP cells (NPCs) were isolated and identified based on specific cellular markers. Furthermore, mRNA-seq was performed to profile gene expression in these cells. GO annotation and KEGG pathway analysis were employed to perform functional enrichment analysis of the differentially expressed genes (DEGs). Cell viability was assessed using the CCK-8 assay. An in vitro cell degeneration model was established by treating NPCs with TBHP. Analysis of specific marker expression was performed using Western blotting, immunohistochemistry, and immunofluorescence. We found that the number of NCs in degenerated NP tissues was significantly reduced compared to those in normal NP tissues, but a small amount of notochordal cell markers could still be detected. Analysis of sequencing data identified 2391 upregulated and 3813 downregulated DEGs. GO enrichment analysis indicated that these DEGs were significantly associated with regulatory signals including cellular senescence and oxidative stress. KEGG pathway analysis further revealed that the DEGs were primarily enriched in the TNF and HIF-1 signaling pathways. Subsequent screening identified the top 10 key genes potentially related to IDD: Sod2, Cxcl12, Spp1, Fn1, Cat, Il6, Ccl2, Igf1, Fgf2, and Acta2. Collectively, our findings establish a clear link between SOD2/CAT and the pathogenesis of IDD. SOD2 and CAT may serve as promising new potential therapeutic targets for IDD by inhibiting oxidative stress and cellular senescence in NPCs.

Background: Polyamide 6 microplastics (PA6-MPs), as emerging environmental pollutants, have attracted increasing attention due to their potential health risks. Their accumulation in human intervertebral disc tissue (86.4 particles/g) suggests a possible role in intervertebral disc degeneration (IVDD). However, direct evidence and mechanistic understanding remain limited. This study aimed to investigate the association between PA6-MPs exposure and IVDD, based on the hypothesis that PA6-MPs promote IVDD progression by targeting key regulatory molecules and disrupting cellular homeostasis. Methods: Potential PA6-related targets were predicted using multiple public databases, and IVDD-related differentially expressed genes were obtained from the GEO database. Overlapping targets were identified and analyzed through protein–protein interaction (PPI) network construction, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to screen core targets and pathways. Molecular docking was performed to evaluate PA6–protein binding. In vitro validation was conducted using primary human nucleus pulposus cells exposed to PA6-MPs, with cell viability, proliferation, and phenotypic changes assessed by CCK-8, EdU, live/dead staining, and immunofluorescence (IF). Results: A total of 222 PA6-related targets and 1035 IVDD-associated genes were identified, yielding 10 overlapping targets. Four core targets, including NR3C1 and HDAC1, were selected. Molecular docking and experiments demonstrated stable binding and concentration-dependent inhibition of cell viability and proliferation. Conclusion: PA6-MPs may accelerate IVDD progression in a concentration-dependent manner by targeting key molecules and perturbing inflammatory homeostasis. These findings link environmental exposure to IVDD and provide a basis for future risk assessment and targeted intervention strategies.

Intervertebral disc degeneration is a major pathological contributor to low back pain and functional impairment, yet its complex molecular mechanisms have not been fully elucidated. Heat shock proteins, as important molecular chaperones and core regulators of cellular stress responses, exhibit dual protective and pathogenic roles in the process of intervertebral disc degeneration. This review summarizes the expression changes and related regulatory networks of heat shock protein family members such as HSP70, HSP90, HSP27 and GRP78 in nucleus pulposus and annulus fibrosus cells, comprehensively discussing their involvement in the molecular mechanisms of intervertebral disc degeneration by influencing key processes such as cellular homeostasis, inflammatory responses, apoptosis, autophagy, and the synthesis and degradation of the extracellular matrix. Furthermore, this review highlights HSP-centered proteostasis regulation as an emerging therapeutic framework for IVDD and discusses how HSP modulation may be integrated with biomaterials, physical stimulation, and regenerative strategies. However, direct IVDD-specific evidence for certain HSP members remains limited, and this review also highlights current knowledge gaps and future research directions for HSP-centered proteostasis regulation.