{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T12:32:01Z","timestamp":1793968321667,"version":"4.8.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,30]],"date-time":"2023-05-30T00:00:00Z","timestamp":1685404800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Intervertebral disc degeneration (IDD) is one of the most common health problems in the elderly and a major causative factor in low back pain (LBP). An increasing number of studies have shown that IDD is closely associated with autophagy and immune dysregulation. Therefore, the aim of this study was to identify autophagy-related biomarkers and gene regulatory networks in IDD and potential therapeutic targets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We obtained the gene expression profiles of IDD by downloading the datasets GSE176205 and GSE167931 from the Gene Expression Omnibus (GEO) public database. Subsequently, differentially expressed genes (DEGs) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, gene ontology (GO), and gene set enrichment analysis (GSEA) were performed to explore the biological functions of DEGs. Differentially expressed autophagy-related genes (DE-ARGs) were then crossed with the autophagy gene database. The hub genes were screened using the DE-ARGs protein\u2013protein interaction (PPI) network. The correlation between the hub genes and immune infiltration and the construction of the gene regulatory network of the hub genes were confirmed. Finally, quantitative PCR (qPCR) was used to validate the correlation of hub genes in a rat IDD model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We obtained 636 DEGs enriched in the autophagy pathway. Our analysis revealed 30 DE-ARGs, of which six hub genes (<jats:italic>MAPK8<\/jats:italic>, <jats:italic>CTSB<\/jats:italic>, <jats:italic>PRKCD<\/jats:italic>, <jats:italic>SNCA<\/jats:italic>, <jats:italic>CAPN1<\/jats:italic>, and <jats:italic>EGFR<\/jats:italic>) were identified using the MCODE plugin. Immune cell infiltration analysis revealed that there was an increased proportion of CD8<jats:sup>+<\/jats:sup> T cells and M0 macrophages in IDD, whereas CD4<jats:sup>+<\/jats:sup> memory T cells, neutrophils, resting dendritic cells, follicular helper T cells, and monocytes were much less abundant. Subsequently, the competitive endogenous RNA (ceRNA) network was constructed using 15 long non-coding RNAs (lncRNAs) and 21 microRNAs (miRNAs). In quantitative PCR (qPCR) validation, two hub genes, <jats:italic>MAPK8<\/jats:italic> and <jats:italic>CAPN1<\/jats:italic>, were shown to be consistent with the bioinformatic analysis results.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study identified <jats:italic>MAPK8<\/jats:italic> and <jats:italic>CAPN1<\/jats:italic> as key biomarkers of IDD. These key hub genes may be potential therapeutic targets for IDD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1188774","type":"journal-article","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T13:26:45Z","timestamp":1685539605000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":31,"title":["MAPK8 and CAPN1 as potential biomarkers of intervertebral disc degeneration overlapping immune infiltration, autophagy, and ceRNA"],"prefix":"10.3389","volume":"14","author":[{"given":"Yuxin","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongyi","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruonan","family":"Ning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longyu","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichen","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobing","family":"Xi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiwei","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30480-X","article-title":"What low back pain is and why we need to pay attention","volume":"391","author":"Hartvigsen","year":"2018","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/00007632-199506000-00022","article-title":"Aging and degeneration of the human intervertebral disc","volume":"20","author":"Buckwalter","year":"1995","journal-title":"Spine (Phila Pa 1976)"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.14488","article-title":"Angiopoietin-like protein 8 expression and association with extracellular matrix metabolism and inflammation during intervertebral disc degeneration","volume":"23","author":"Liao","year":"2019","journal-title":"J Cell Mol Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S1529-9430(01)00021-3","article-title":"Biochemistry of intervertebral disc degeneration and the potential for gene therapy applications","volume":"1","author":"Cassinelli","year":"2001","journal-title":"Spine J"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2003558","article-title":"Degenerative cervical spondylosis","volume":"383","author":"Theodore","year":"2020","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.3390\/polym11071151","article-title":"Disordered mechanical stress and tissue engineering therapies in intervertebral disc degeneration","volume":"11","author":"Zhao","year":"2019","journal-title":"Polymers (Basel)"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.7150\/thno.33638","article-title":"Exosomes from mesenchymal stem cells modulate endoplasmic reticulum stress to protect against nucleus pulposus cell death and ameliorate intervertebral disc degeneration in vivo","volume":"9","author":"Liao","year":"2019","journal-title":"Theranostics"},{"key":"B8","doi-asserted-by":"publisher","first-page":"16107","DOI":"10.1038\/cddiscovery.2016.107","article-title":"IAPP modulates cellular autophagy, apoptosis, and extracellular matrix metabolism in human intervertebral disc cells","volume":"3","author":"Wu","year":"2017","journal-title":"Cell Death Discovery"},{"key":"B9","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1186\/s13075-018-1743-4","article-title":"The inflammatory response in the regression of lumbar disc herniation","volume":"20","author":"Cunha","year":"2018","journal-title":"Arthritis Res Ther"},{"key":"B10","doi-asserted-by":"publisher","first-page":"119266","DOI":"10.1016\/j.lfs.2021.119266","article-title":"Autophagy as a potential therapeutic target in intervertebral disc degeneration","volume":"273","author":"Gong","year":"2021","journal-title":"Life Sci"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2166817","DOI":"10.1155\/2022\/2166817","article-title":"The role of oxidative stress in intervertebral disc degeneration","volume":"2022","author":"Cao","year":"2022","journal-title":"Oxid Med Cell Longev"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2016.04.005","article-title":"Genetic factors in intervertebral disc degeneration","volume":"3","author":"Feng","year":"2016","journal-title":"Genes Dis"},{"key":"B13","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.jpha.2019.07.002","article-title":"Karacoline, identified by network pharmacology, reduces degradation of the extracellular matrix in intervertebral disc degeneration via the NF-\u03baB signaling pathway","volume":"10","author":"Zhou","year":"2020","journal-title":"J Pharm Anal"},{"key":"B14","doi-asserted-by":"publisher","first-page":"27","DOI":"10.7150\/thno.48987","article-title":"Small molecule-based treatment approaches for intervertebral disc degeneration: current options and future directions","volume":"11","author":"Kamali","year":"2021","journal-title":"Theranostics"},{"key":"B15","doi-asserted-by":"publisher","first-page":"4139","DOI":"10.1038\/s41467-018-06556-9","article-title":"ATR\/Chk1 signaling induces autophagy through sumoylated RhoB-mediated lysosomal translocation of TSC2 after DNA damage","volume":"9","author":"Liu","year":"2018","journal-title":"Nat Commun"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2239","article-title":"Self-eating and self-killing: crosstalk between autophagy and apoptosis","volume":"8","author":"Maiuri","year":"2007","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.10.026","article-title":"Autophagy: renovation of cells and tissues","volume":"147","author":"Mizushima","year":"2011","journal-title":"Cell"},{"key":"B18","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.cell.2018.09.048","article-title":"Biological functions of autophagy genes: a disease perspective","volume":"176","author":"Levine","year":"2019","journal-title":"Cell"},{"key":"B19","doi-asserted-by":"publisher","first-page":"315896","DOI":"10.1155\/2014\/315896","article-title":"Antioxidant supplement inhibits skeletal muscle constitutive autophagy rather than fasting-induced autophagy in mice","volume":"2014","author":"Qi","year":"2014","journal-title":"Oxid Med Cell Longev"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2020.12.002","article-title":"Role of autophagy in intervertebral disc and cartilage function: implications in health and disease","author":"Madhu","year":"2021","journal-title":"Matrix Biol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.765382","article-title":"An oxidative stress-related gene pair (CCNB1\/PKD1), competitive endogenous RNAs, and immune-infiltration patterns potentially regulate intervertebral disc degeneration development","volume":"12","author":"Cao","year":"2021","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/s41419-020-2543-8","article-title":"The circular RNA FAM169A functions as a competitive endogenous RNA and regulates intervertebral disc degeneration by targeting miR-583 and BTRC","volume":"11","author":"Guo","year":"2020","journal-title":"Cell Death Dis"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1042\/CS20160918","article-title":"The noncoding RNA linc-ADAMTS5 cooperates with RREB1 to protect from intervertebral disc degeneration through inhibiting ADAMTS5 expression","volume":"131","author":"Wang","year":"2017","journal-title":"Clin Sci (Lond)"},{"key":"B24","doi-asserted-by":"publisher","first-page":"100141","DOI":"10.1016\/j.xinn.2021.100141","article-title":"clusterProfiler 4.0: a universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1590\/1414-431X20122429","article-title":"Experimental model of intervertebral disc degeneration by needle puncture in wistar rats","volume":"46","author":"Issy","year":"2013","journal-title":"Braz J Med Biol Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2021.1872227","article-title":"HIF1A alleviates compression-induced apoptosis of nucleus pulposus derived stem cells via upregulating autophagy","volume":"17","author":"He","year":"2021","journal-title":"Autophagy"},{"key":"B27","doi-asserted-by":"publisher","first-page":"5643","DOI":"10.1038\/s41467-019-13476-9","article-title":"Sensory innervation in porous endplates by netrin-1 from osteoclasts mediates PGE2-induced spinal hypersensitivity in mice","volume":"10","author":"Ni","year":"2019","journal-title":"Nat Commun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1097\/00007632-199202000-00010","article-title":"Cost-effectiveness analysis of extended conservative therapy versus surgical intervention in the management of herniated lumbar intervertebral disc","volume":"17","author":"Shvartzman","year":"1992","journal-title":"Spine (Phila Pa 1976)"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30488-4","article-title":"Low back pain: a call for action","volume":"391","author":"Buchbinder","year":"2018","journal-title":"Lancet"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.7326\/AITC202108170","article-title":"Low back pain","volume":"174","author":"Chou","year":"2021","journal-title":"Ann Intern Med"},{"key":"B31","doi-asserted-by":"publisher","first-page":"144634","DOI":"10.1016\/j.gene.2020.144634","article-title":"Lumbar intervertebral disc mRNA sequencing identifies the regulatory pathway in patients with disc herniation and spondylolisthesis","volume":"750","author":"Bydon","year":"2020","journal-title":"Gene"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/jsp2.1146","article-title":"Transcriptional profiling of intervertebral disc in a post-traumatic early degeneration organ culture model","volume":"4","author":"Cui","year":"2021","journal-title":"JOR Spine"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1080\/21655979.2022.2031396","article-title":"Tetrandrine reduces oxidative stress, apoptosis, and extracellular matrix degradation and improves intervertebral disc degeneration by inducing autophagy","volume":"13","author":"Liu","year":"2022","journal-title":"Bioengineered"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/jsp2.1196","article-title":"The involvement of immune system in intervertebral disc herniation and degeneration","volume":"5","author":"Ye","year":"2022","journal-title":"JOR Spine"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.7150\/ijms.42238","article-title":"The immune privilege of the intervertebral disc: implications for intervertebral disc degeneration treatment","volume":"17","author":"Sun","year":"2020","journal-title":"Int J Med Sci"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1097\/BRS.0000000000000832","article-title":"Can bacterial infection by low virulent organisms be a plausible cause for symptomatic disc degeneration? a systematic review","volume":"40","author":"Ganko","year":"2015","journal-title":"Spine (Phila Pa 1976)"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0270982","article-title":"Different phylotypes of cutibacterium acnes cause different modic changes in intervertebral disc degeneration","volume":"17","author":"Lan","year":"2022","journal-title":"PloS One"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.908211","article-title":"Intervertebral disc cell chondroptosis elicits neutrophil response in staphylococcus aureus spondylodiscitis","volume":"13","author":"Schweizer","year":"2022","journal-title":"Front Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3337","article-title":"Robust enumeration of cell subsets from tissue expression profiles","volume":"12","author":"Newman","year":"2015","journal-title":"Nat Methods"},{"key":"B40","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41419-018-1246-x","article-title":"Transgenic mice overexpressing human TNF-alpha experience early onset spontaneous intervertebral disc herniation in the absence of overt degeneration","volume":"10","author":"Gorth","year":"2018","journal-title":"Cell Death Dis"},{"key":"B41","doi-asserted-by":"publisher","first-page":"106537","DOI":"10.1016\/j.phrs.2022.106537","article-title":"Hsa-let-7f-1-3p targeting the circadian gene Bmal1 mediates intervertebral disc degeneration by regulating autophagy","volume":"186","author":"Mei","year":"2022","journal-title":"Pharmacol Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-022-01725-0","article-title":"Inhibition of miR-130b-3p restores autophagy and attenuates intervertebral disc degeneration through mediating ATG14 and PRKAA1","volume":"27","author":"Wu","year":"2022","journal-title":"Apoptosis"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.27466","article-title":"LINC00641 regulates autophagy and intervertebral disc degeneration by acting as a competitive endogenous RNA of miR-153-3p under nutrition deprivation stress","volume":"234","author":"Wang","year":"2019","journal-title":"J Cell Physiol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"102679","DOI":"10.1016\/j.ebiom.2020.102679","article-title":"CircRNA-CIDN mitigated compression loading-induced damage in human nucleus pulposus cells via miR-34a-5p\/SIRT1 axis","volume":"53","author":"Xiang","year":"2020","journal-title":"EBioMedicine"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s12276-018-0125-y","article-title":"CircularRNA_104670 plays a critical role in intervertebral disc degeneration by functioning as a ceRNA","volume":"50","author":"Song","year":"2018","journal-title":"Exp Mol Med"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1080\/21655979.2021.1899533","article-title":"Differentially-expressed mRNAs, microRNAs and long noncoding RNAs in intervertebral disc degeneration identified by RNA-sequencing","volume":"12","author":"Li","year":"2021","journal-title":"Bioengineered"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1995","DOI":"10.1007\/s11010-021-04058-9","article-title":"LncRNA LINC00324 is upregulated in intervertebral disk degeneration and upregulates FasL in nucleus pulposus cells","volume":"476","author":"Chen","year":"2021","journal-title":"Mol Cell Biochem"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1080\/15476286.2021.1898176","article-title":"MicroRNA-140-3p alleviates intervertebral disc degeneration via KLF5\/N-cadherin\/MDM2\/Slug axis","volume":"18","author":"Wang","year":"2021","journal-title":"RNA Biol"},{"key":"B49","doi-asserted-by":"publisher","first-page":"2153337","DOI":"10.1155\/2022\/2153337","article-title":"LINC01535 attenuates ccRCC progression through regulation of the miR-146b-5p\/TRIM2 axis and inactivation of the PI3K\/Akt pathway","volume":"2022","author":"Zhang","year":"2022","journal-title":"J Oncol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.4155\/fmc.15.132","article-title":"JNK pathway signaling: a novel and smarter therapeutic targets for various biological diseases","volume":"7","author":"Kumar","year":"2015","journal-title":"Future Med Chem"},{"key":"B51","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1186\/s12967-016-0833-9","article-title":"IL-17 mediates inflammatory reactions via p38\/c-fos and JNK\/c-jun activation in an AP-1-dependent manner in human nucleus pulposus cells","volume":"14","author":"Li","year":"2016","journal-title":"J Transl Med"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1055\/s-0034-1376584","article-title":"The roles of MAPKs in rabbit nucleus pulposus cell apoptosis induced by high osmolality","volume":"18","author":"Dong","year":"2014","journal-title":"Eur Rev For Med Pharmacol Sci"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.40189","article-title":"Syndecan-4 is a novel therapeutic target for intervertebral disc degeneration via suppressing JNK\/p53 pathway","volume":"16","author":"Ge","year":"2020","journal-title":"Int J Biol Sci"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.120.032749","article-title":"CAPN1 (Calpain1)-mediated impairment of autophagic flux contributes to cerebral ischemia-induced neuronal damage","volume":"52","author":"Liu","year":"2021","journal-title":"Stroke"},{"key":"B55","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1007\/s00395-022-00948-1","article-title":"Mitochondrial calpain-1 activates NLRP3 inflammasome by cleaving ATP5A1 and inducing mitochondrial ROS in CVB3-induced myocarditis","volume":"117","author":"Liu","year":"2022","journal-title":"Basic Res Cardiol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1188774\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T13:26:51Z","timestamp":1685539611000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1188774\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,30]]},"references-count":55,"alternative-id":["10.3389\/fimmu.2023.1188774"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1188774","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,30]]},"article-number":"1188774"}}