{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T00:57:46Z","timestamp":1794013066595,"version":"4.8.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T00:00:00Z","timestamp":1668124800000},"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. Genet."],"abstract":"<jats:p>Ankylosing spondylitis (AS) is a chronic progressive autoimmune disease with insidious onset, high rates of disability among patients, unknown pathogenesis, and no effective treatment. Ferroptosis is a novel type of regulated cell death that is associated with various cancers and diseases. However, its relation to AS is not clear. In the present study, we identified two potential therapeutic targets for AS based on genes associated with ferroptosis and explored their association with immune cells and immune cell infiltration (ICI). We studied gene expression profiles of two cohorts of patients with AS (GSE25101 and GSE41038) derived from the gene expression omnibus database, and ferroptosis-associated genes (FRGs) were obtained from the FerrDb database. LASSO regression analysis was performed to build predictive models for AS based on FRGs, and the ferroptosis level in each sample was assessed <jats:italic>via<\/jats:italic> single-sample gene set enrichment analysis. Weighted gene co-expression network and protein-protein interaction network analyses were performed for screening; two key genes, DDIT3 and HSPB1, were identified in patients with AS. The relationship between key genes and ICI levels was assessed using the CIBERSORT algorithm, followed by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Finally, DDIT3 and HSPB1 were identified as diagnostic markers and potential therapeutic targets for AS. DDIT3 was highly positively correlated with the infiltration levels of various immune cells, while HSPB1 was negatively correlated with the infiltration levels of several different types of immune cells. In conclusion, DDIT3 and HSPB1 may induce ferroptosis in the cells of patients with AS <jats:italic>via<\/jats:italic> changes in the inflammatory response in the immune microenvironment, and these genes could serve as molecular targets for AS therapy.<\/jats:p>","DOI":"10.3389\/fgene.2022.948290","type":"journal-article","created":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T07:14:34Z","timestamp":1668150874000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Role of ferroptosis-associated genes in ankylosing spondylitis and immune cell infiltration"],"prefix":"10.3389","volume":"13","author":[{"given":"Qiaochu","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaohua","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linbang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjin","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanhuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengxue","family":"Quan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.1038\/cdd.2012.67","article-title":"C\/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in \u03b2-cells","volume":"19","author":"Allagnat","year":"2012","journal-title":"Cell Death Differ."},{"key":"B2","doi-asserted-by":"publisher","first-page":"D760","DOI":"10.1093\/nar\/gkl887","article-title":"NCBI GEO: mining tens of millions of expression profiles--database and tools update","volume":"35","author":"Barrett","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1093\/bioinformatics\/19.2.185","article-title":"A comparison of normalization methods for high density oligonucleotide array data based on variance and bias","volume":"19","author":"Bolstad","year":"2003","journal-title":"Bioinformatics"},{"key":"B4","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/s12918-017-0420-6","article-title":"An additional k-means clustering step improves the biological features of WGCNA gene co-expression networks","volume":"11","author":"Bot\u00eda","year":"2017","journal-title":"BMC Syst. Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2672","DOI":"10.4049\/jimmunol.1002653","article-title":"Th17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis","volume":"186","author":"Bowness","year":"2011","journal-title":"J. Immunol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1016\/j.berh.2018.09.005","article-title":"Genetics in ankylosing spondylitis - current state of the art and translation into clinical outcomes","volume":"31","author":"Brown","year":"2017","journal-title":"Best. Pract. Res. Clin. Rheumatol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.tibs.2016.01.003","article-title":"Heat shock proteins promote cancer: It\u2019s a protection racket","volume":"41","author":"Calderwood","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"3586","DOI":"10.1002\/art.21395","article-title":"Expansion and enhanced survival of natural killer cells expressing the killer immunoglobulin-like receptor KIR3DL2 in spondylarthritis","volume":"52","author":"Chan","year":"2005","journal-title":"Arthritis Rheum."},{"key":"B9","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1038\/s41571-020-00462-0","article-title":"Broadening horizons: the role of ferroptosis in cancer","volume":"18","author":"Chen","year":"2021","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1093\/rheumatology\/ket387","article-title":"Global prevalence of ankylosing spondylitis","volume":"53","author":"Dean","year":"2014","journal-title":"Rheumatology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1016\/j.ejim.2011.06.006","article-title":"Extra-articular manifestations of ankylosing spondylitis: prevalence, characteristics and therapeutic implications","volume":"22","author":"El Maghraoui","year":"2011","journal-title":"Eur. J. Intern. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"24","DOI":"10.5606\/ArchRheumatol.2016.5562","article-title":"Diagnostic delay in ankylosing spondylitis: related factors and prognostic outcomes","volume":"31","author":"Fallahi","year":"2016","journal-title":"Arch. Rheumatol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v033.i01","article-title":"Regularization paths for generalized linear models via coordinate descent","volume":"33","author":"Friedman","year":"2010","journal-title":"J. Stat. Softw."},{"key":"B14","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/s41065-021-00201-0","article-title":"Identification and validation of hub genes of synovial tissue for patients with osteoarthritis and rheumatoid arthritis","volume":"158","author":"Ge","year":"2021","journal-title":"Hereditas"},{"key":"B15","doi-asserted-by":"publisher","first-page":"3001","DOI":"10.1093\/bioinformatics\/bti422","article-title":"Penalized Cox regression analysis in the high-dimensional and low-sample size settings, with applications to microarray gene expression data","volume":"21","author":"Gui","year":"2005","journal-title":"Bioinformatics"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1570","DOI":"10.1056\/NEJMra0901217","article-title":"Cell death","volume":"361","author":"Hotchkiss","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/cdd.2008.150","article-title":"Classification of cell death: recommendations of the nomenclature committee on cell death 2009","volume":"16","author":"Kroemer","year":"2009","journal-title":"Cell Death Differ."},{"key":"B18","doi-asserted-by":"publisher","first-page":"622306","DOI":"10.3389\/fimmu.2021.622306","article-title":"The role of natural killer cells in autoimmune diseases","volume":"12","author":"Kucuksezer","year":"2021","journal-title":"Front. Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1136\/ard.2008.091793","article-title":"Physical function in ankylosing spondylitis is independently determined by both disease activity and radiographic damage of the spine","volume":"68","author":"Landew\u00e9","year":"2009","journal-title":"Ann. Rheum. Dis."},{"key":"B20","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinforma."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1158\/1541-7786.MCR-18-0055","article-title":"Ferroptosis-Induced endoplasmic reticulum stress: cross-talk between ferroptosis and apoptosis","volume":"16","author":"Lee","year":"2018","journal-title":"Mol. Cancer Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1296","DOI":"10.1080\/15548627.2019.1671643","article-title":"BIRC5\/Survivin is a novel ATG12-ATG5 conjugate interactor and an autophagy-induced DNA damage suppressor in human cancer and mouse embryonic fibroblast cells","volume":"16","author":"Lin","year":"2020","journal-title":"Autophagy"},{"key":"B24","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1038\/nrrheum.2009.258","article-title":"Disease modification in ankylosing spondylitis","volume":"6","author":"Maksymowych","year":"2010","journal-title":"Nat. Rev. Rheumatol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1038\/s41587-019-0114-2","article-title":"Determining cell type abundance and expression from bulk tissues with digital cytometry","volume":"37","author":"Newman","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1136\/ard.48.1.35","article-title":"Polymorphonuclear leucocyte motility in men with ankylosing spondylitis","volume":"48","author":"Pease","year":"1989","journal-title":"Ann. Rheum. Dis."},{"key":"B27","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/j.apmr.2017.07.015","article-title":"Effectiveness of exercise programs in ankylosing spondylitis: a meta-analysis of randomized controlled trials","volume":"99","author":"P\u00e9courneau","year":"2018","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"B28","doi-asserted-by":"publisher","first-page":"R57","DOI":"10.1186\/ar3309","article-title":"Whole blood transcriptional profiling in ankylosing spondylitis identifies novel candidate genes that might contribute to the inflammatory and tissue-destructive disease aspects","volume":"13","author":"Pimentel-Santos","year":"2011","journal-title":"Arthritis Res. Ther."},{"key":"B29","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1038\/nrrheum.2017.56","article-title":"Pathogenesis of ankylosing spondylitis - recent advances and future directions","volume":"13","author":"Ranganathan","year":"2017","journal-title":"Nat. Rev. Rheumatol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"m4447","DOI":"10.1136\/bmj.m4447","article-title":"Axial spondyloarthritis: new advances in diagnosis and management","volume":"372","author":"Ritchlin","year":"2021","journal-title":"BMJ"},{"key":"B31","doi-asserted-by":"publisher","first-page":"10","DOI":"10.2106\/JBJS.F.00019","article-title":"Histology and pathology of the human intervertebral disc","volume":"88","author":"Roberts","year":"2006","journal-title":"J. Bone Jt. Surg. Am."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.3390\/genes13081373","article-title":"New insights into the regulatory role of ferroptosis in ankylosing spondylitis via consensus clustering of ferroptosis-related genes and weighted gene Co-expression network analysis","volume":"13","author":"Rong","year":"2022","journal-title":"Genes"},{"key":"B33","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.cell.2017.09.021","article-title":"Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease","volume":"171","author":"Stockwell","year":"2017","journal-title":"Cell"},{"key":"B34","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B35","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.freeradbiomed.2020.02.027","article-title":"Lipid peroxidation and ferroptosis: the role of GSH and GPx4","volume":"152","author":"Ursini","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.3892\/mmr.2018.9136","article-title":"Identification of genes and signaling pathways associated with the pathogenesis of juvenile spondyloarthritis","volume":"18","author":"Wang","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1093\/bioinformatics\/btq170","article-title":"ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking","volume":"26","author":"Wilkerson","year":"2010","journal-title":"Bioinformatics"},{"key":"B38","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1038\/cdd.2015.158","article-title":"Ferroptosis: process and function","volume":"23","author":"Xie","year":"2016","journal-title":"Cell Death Differ."},{"key":"B39","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.jprot.2014.09.014","article-title":"Up-regulation of fatty acid oxidation in the ligament as a contributing factor of ankylosing spondylitis: a comparative proteomic study","volume":"113","author":"Xu","year":"2015","journal-title":"J. Proteomics"},{"key":"B40","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1038\/s41419-020-02993-x","article-title":"Oxidative stress-mediated mitochondrial dysfunction facilitates mesenchymal stem cell senescence in ankylosing spondylitis","volume":"11","author":"Ye","year":"2020","journal-title":"Cell Death Dis."},{"key":"B41","doi-asserted-by":"publisher","first-page":"e12761","DOI":"10.1111\/cpr.12761","article-title":"Ferroptosis: Final destination for cancer?","volume":"53","author":"Ye","year":"2020","journal-title":"Cell Prolif."},{"key":"B42","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics J. Integr. Biol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1093\/hmg\/ddaa272","article-title":"SNP-adjacent super enhancer network mediates enhanced osteogenic differentiation of MSCs in ankylosing spondylitis","volume":"30","author":"Yu","year":"2021","journal-title":"Hum. Mol. Genet."},{"key":"B44","doi-asserted-by":"publisher","first-page":"393","DOI":"10.3109\/02656736.2014.956810","article-title":"Whole body hyperthermia treatment increases interleukin 10 and toll-like receptor 4 expression in patients with ankylosing spondylitis: a pilot study","volume":"30","author":"Zauner","year":"2014","journal-title":"Int. J. Hyperth."},{"key":"B45","doi-asserted-by":"publisher","first-page":"baaa021","DOI":"10.1093\/database\/baaa021","article-title":"FerrDb: a manually curated resource for regulators and markers of ferroptosis and ferroptosis-disease associations","volume":"2020","author":"Zhou","year":"2020","journal-title":"Database."},{"key":"B46","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1097\/BOR.0b013e3283028328","article-title":"Assessment and treatment of ankylosing spondylitis: current status and future directions","volume":"20","author":"Zochling","year":"2008","journal-title":"Curr. Opin. Rheumatol."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.948290\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T07:14:39Z","timestamp":1668150879000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.948290\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,11]]},"references-count":46,"alternative-id":["10.3389\/fgene.2022.948290"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.948290","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,11]]},"article-number":"948290"}}