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In this study, we integrated single\u2010cell RNA sequencing (scRNA\u2010Seq), transcriptomics, and Mendelian randomization (MR) analysis to investigate the immune mechanisms and identify key biomolecules involved in IVDD. Single\u2010cell analysis of nucleus pulposus (NP) samples from four patients with disc degeneration revealed 20 distinct clusters, which were categorized into four primary cell types: blood cells, chondrocytes, endothelial cells, and stromal cells. These cell types were shown to play crucial roles in the immune microenvironment, as evidenced by ligand\u2010receptor interaction analysis, which delineated potential intercellular communication networks. By combining eQTL (expression Quantitative Trait Loci) data with FinnGen datasets in MR analysis, we identified five key genes (CD83, COL6A1, LAPTM5, NPC2, ZFAND2A) significantly associated with IVDD risk. The expression of these genes in NP tissues showed strong correlations with immune cell infiltration. Protein\u2010level validation confirmed the upregulation of COL6A1, LAPTM5, and ZFAND2A in degenerative NP tissues. Functional enrichment analysis revealed their involvement in multiple immune\u2010related pathways. Additionally, co\u2010expression analysis identified relationships between these key genes and critical immune genes, such as CD14 and CD274. This study leverages multi\u2010omics integration to uncover the immune regulatory mechanisms underlying IVDD, providing valuable insights into the role of biomolecules in the pathogenesis of disc degeneration and offering potential for novel diagnostic and therapeutic strategies.<\/jats:p>","DOI":"10.1096\/fj.202500320r","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T16:34:20Z","timestamp":1761150860000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<scp>COL6A1<\/scp>\n                    ,\n                    <scp>LAPTM5<\/scp>\n                    , and\n                    <scp>ZFAND2A<\/scp>\n                    as Crucial Biomolecules Driving Immunoregulation in Human Nucleus Pulposus Degeneration"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3051-9183","authenticated-orcid":false,"given":"Ze\u2010Yu","family":"Lu","sequence":"first","affiliation":[{"name":"Spine Center, Xinhua Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1783-3773","authenticated-orcid":false,"given":"Peng\u2010Bo","family":"Chen","sequence":"additional","affiliation":[{"name":"Spine Center, Xinhua Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3579-5910","authenticated-orcid":false,"given":"Qing\u2010Yin","family":"Xu","sequence":"additional","affiliation":[{"name":"Spine Center, Xinhua Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9315-177X","authenticated-orcid":false,"given":"Muradil","family":"Mardan","sequence":"additional","affiliation":[{"name":"Spine Center, Xinhua Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6599-6405","authenticated-orcid":false,"given":"Meng\u2010Jia","family":"You","sequence":"additional","affiliation":[{"name":"Department of Medical Technology, School of Exercise and Health Shanghai University of Sport  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0292-4691","authenticated-orcid":false,"given":"Bo","family":"Li","sequence":"additional","affiliation":[{"name":"Spine Center, Xinhua Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6653-1881","authenticated-orcid":false,"given":"Sheng\u2010Dan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Spine Center, Xinhua Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6503-7443","authenticated-orcid":false,"given":"Lei\u2010Sheng","family":"Jiang","sequence":"additional","affiliation":[{"name":"Spine Center, Xinhua Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8355-2967","authenticated-orcid":false,"given":"Xin\u2010Feng","family":"Zheng","sequence":"additional","affiliation":[{"name":"Spine Center, Xinhua Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,22]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(18)30480\u2010x"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572\u2010018\u20100052\u20101"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/BRS.0b013e3181a01b3f"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2010.137836"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jsp2.1242"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00776\u2010006\u20101055\u20104"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00441\u2010022\u201003662\u20105"},{"key":"e_1_2_10_9_1","first-page":"2601","article-title":"Volvo Award in Clinical Sciences","volume":"20","author":"Batti\u00e9 M. 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