{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:43:53Z","timestamp":1784249033794,"version":"3.55.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T00:00:00Z","timestamp":1758240000000},"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>Osteomyelitis (OM) is a debilitating infectious disease characterized by inflammation of the bone and bone marrow. Emerging evidence suggests that multiple forms of programmed cell death (PCD) contribute to its pathogenesis. However, the specific roles and interactions of these PCD types in OM remain largely undefined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Microarray-based transcriptome datasets related to OM were retrieved from the Gene Expression Omnibus (GEO) database. Thirteen PCD modalities were defined from the literature and specialized databases, including classical forms (e.g., apoptosis, autophagy) and non-classical forms (e.g., cuproptosis, entosis, ferroptosis). Gene Set Variation Analysis (GSVA) was used to evaluate pathway activities in OM, and their associations with immune infiltration, inflammation-related gene expression, and diagnostic value were systematically assessed. Weighted gene co-expression network analysis (WGCNA) was performed to identify essential modules and hub genes. A diagnostic model was constructed using machine learning with SHapley Additive exPlanations (SHAP), and candidate genes were validated in clinical peripheral blood samples using polymerase chain reaction (PCR).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Eight core PCD pathways were significantly associated with OM, mainly represented by apoptosis, autophagy, and non-classical forms such as cuproptosis and entosis. By integrating WGCNA with SHAP analysis, five hub genes (SORT1, KIF1B, TMEM106B, NPC1, and ATP6V0B) were identified as key diagnostic candidates. qPCR validation confirmed their significantly different expression between OM patients and healthy controls, supporting their utility as diagnostic biomarkers for early detection and treatment stratification.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study provides a comprehensive landscape of PCD involvement in OM, identifies novel diagnostic biomarkers, and highlights potential therapeutic targets for clinical intervention.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1630172","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T04:12:55Z","timestamp":1758255175000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification and analysis of diverse cell death patterns in osteomyelitis via microarray-based transcriptome profiling and clinical data"],"prefix":"10.3389","volume":"16","author":[{"given":"Tianxuan","family":"Feng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peisheng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengfei","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(04)16727-5","article-title":"Osteomyelitis","volume":"364","author":"Lew","year":"2004","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.jgar.2021.03.030","article-title":"Staphylococcus aureus clones causing osteomyelitis: a literature review (2000-2020)","volume":"26","author":"Pimentel de Araujo","year":"2021","journal-title":"J Glob Antimicrob Resist"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.2106\/JBJS.N.01350","article-title":"Trends in the epidemiology of osteomyelitis: a population-based study, 1969 to 2009","volume":"97","author":"Kremers","year":"2015","journal-title":"J Bone Joint Surg Am"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00932-19","article-title":"Staphylococcus aureus osteomyelitis: bone, bugs, and surgery","volume":"88","author":"Urish","year":"2020","journal-title":"Infect Immun"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-0270-8","article-title":"Emerging connectivity of programmed cell death pathways and its physiological implications","volume":"21","author":"Bedoui","year":"2020","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/s41419-024-06712-8","article-title":"Research progress on morphology and mechanism of programmed cell death","volume":"15","author":"Chen","year":"2024","journal-title":"Cell Death Dis"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e70024","DOI":"10.1002\/mco2.70024","article-title":"Programmed cell death: molecular mechanisms, biological functions, diseases, and therapeutic targets","volume":"5","author":"Qian","year":"2024","journal-title":"MedComm"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1972.33","article-title":"Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics","volume":"26","author":"Kerr","year":"1972","journal-title":"Br J Cancer"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines12071546","article-title":"Forms of non-apoptotic cell death and their role in gliomas: presentation of the current state of knowledge","volume":"12","author":"Nafe","year":"2024","journal-title":"Biomedicines"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e13317","DOI":"10.1111\/cmi.13317","article-title":"Intracellular Staphylococcus aureus and host cell death pathways","volume":"23","author":"Soe","year":"2021","journal-title":"Cell Microbiol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1038\/s41420-024-02181-2","article-title":"Repair and regeneration: ferroptosis in the process of remodeling and fibrosis in impaired organs","volume":"10","author":"Yin","year":"2024","journal-title":"Cell Death Discov"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S406562","article-title":"Identification of ferroptosis-related biomarkers for diagnosis and molecular classification of Staphylococcus aureus-induced osteomyelitis","volume":"16","author":"Shi","year":"2023","journal-title":"J Inflammation Res"},{"key":"B13","doi-asserted-by":"publisher","first-page":"e1339","DOI":"10.1002\/iid3.1339","article-title":"Integrative gene expression analysis and animal model reveal immune- and autophagy-related biomarkers in osteomyelitis","volume":"12","author":"Shi","year":"2024","journal-title":"Immun Inflammation Dis"},{"key":"B14","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1.30.1","DOI":"10.1002\/cpbi.5","article-title":"The GeneCards suite: from gene data mining to disease genome sequence analyses","volume":"54","author":"Stelzer","year":"2016","journal-title":"Curr Protoc Bioinf"},{"key":"B16","doi-asserted-by":"publisher","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":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1028","article-title":"The Reactome pathway knowledgebase 2022","volume":"50","author":"Gillespie","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijsu.2022.106936","article-title":"Leveraging diverse cell-death patterns to predict the prognosis and drug sensitivity of triple-negative breast cancer patients after surgery","volume":"107","author":"Zou","year":"2022","journal-title":"Int J Surg"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts034","article-title":"The sva package for removing batch effects and other unwanted variation in high-throughput experiments","volume":"28","author":"Leek","year":"2012","journal-title":"Bioinformatics"},{"key":"B20","doi-asserted-by":"publisher","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"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1070","article-title":"KEGG as a reference resource for gene and protein annotation","volume":"44","author":"Kanehisa","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1055","article-title":"The Gene Ontology Consortium. The Gene Ontology resource: 20 years and still GOing strong","volume":"47","author":"Carbon","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B23","doi-asserted-by":"publisher","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":"B24","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-7","article-title":"GSVA: gene set variation analysis for microarray and RNA-seq data","volume":"14","author":"H\u00e4nzelmann","year":"2013","journal-title":"BMC Bioinf"},{"key":"B25","doi-asserted-by":"publisher","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 Bioinf"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bti623","article-title":"ROCR: visualizing classifier performance in R","volume":"21","author":"Sing","year":"2005","journal-title":"Bioinformatics"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2020.586871","article-title":"Predicting diagnostic gene biomarkers associated with immune infiltration in patients with acute myocardial infarction","volume":"7","author":"Zhao","year":"2020","journal-title":"Front Cardiovasc Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.10.003","article-title":"Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer","volume":"39","author":"Bindea","year":"2013","journal-title":"Immunity"},{"key":"B29","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1038\/nri.2016.107","article-title":"Immunogenic cell death in cancer and infectious disease","volume":"17","author":"Galluzzi","year":"2017","journal-title":"Nat Rev Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2024.111815","article-title":"Examining the causal relationship between circulating immune cells and the susceptibility to osteomyelitis: a Mendelian randomization study","volume":"131","author":"Liu","year":"2024","journal-title":"Int Immunopharmacol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1042\/bj3260001","article-title":"Caspases: the executioners of apoptosis","volume":"326","author":"Cohen","year":"1997","journal-title":"Biochem J"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.110153","article-title":"TWIST1 rescue calcium overload and apoptosis induced by inflammatory microenvironment in S. aureus-induced osteomyelitis","volume":"119","author":"Wang","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jlr.2022.100243","article-title":"Sorting through the extensive and confusing roles of sortilin in metabolic disease","volume":"63","author":"Mitok","year":"2022","journal-title":"J Lipid Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.01507","article-title":"Regulatory roles of sortilin and SorLA in immune-related processes","volume":"10","author":"Talbot","year":"2019","journal-title":"Front Pharmacol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1155333","article-title":"ProBDNF and its receptors in immune-mediated inflammatory diseases: novel insights into the regulation of metabolism and mitochondria","volume":"14","author":"Li","year":"2023","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"e103523","DOI":"10.1371\/journal.pone.0103523","article-title":"Gene expression analysis of children with acute hematogenous osteomyelitis caused by methicillin-resistant Staphylococcus aureus: correlation with clinical severity of illness","volume":"9","author":"Gaviria-Agudelo","year":"2014","journal-title":"PloS One"},{"key":"B37","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1136\/jmedgenet-2019-106769","article-title":"\u2018Kinesinopathies\u2019: emerging role of the kinesin family member genes in birth defects","volume":"57","author":"Kalantari","year":"2020","journal-title":"J Med Genet"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-008-0553-1","article-title":"A germline mutation of the KIF1B beta gene on 1p36 in a family with neural and nonneural tumors","volume":"124","author":"Yeh","year":"2008","journal-title":"Hum Genet"},{"key":"B39","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1038\/s41419-023-06154-8","article-title":"Autophagy: regulator of cell death","volume":"14","author":"Liu","year":"2023","journal-title":"Cell Death Dis"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/nri3532","article-title":"Autophagy in infection, inflammation and immunity","volume":"13","author":"Deretic","year":"2013","journal-title":"Nat Rev Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2014.07.006","article-title":"Lysosome size, motility and stress response regulated by fronto-temporal dementia modifier TMEM106B","volume":"61","author":"Stagi","year":"2014","journal-title":"Mol Cell Neurosci"},{"key":"B42","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1007\/s00018-024-05241-z","article-title":"Physiological and pathological functions of TMEM106B in neurodegenerative diseases","volume":"81","author":"Zhu","year":"2024","journal-title":"Cell Mol Life Sci"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3390\/cells7100162","article-title":"Chronic infections: a possible scenario for autophagy and senescence cross-talk","volume":"7","author":"Aguilera","year":"2018","journal-title":"Cells"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.115121","article-title":"The role of redox-mediated lysosomal dysfunction and therapeutic strategies","volume":"165","author":"He","year":"2023","journal-title":"BioMed Pharmacother"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1186\/s11658-024-00633-2","article-title":"Lysosome quality control in health and neurodegenerative diseases","volume":"29","author":"Ferrari","year":"2024","journal-title":"Cell Mol Biol Lett"},{"key":"B46","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1002\/jcp.30928","article-title":"Lysosome signaling in cell survival and programmed cell death for cellular homeostasis","volume":"238","author":"Patra","year":"2023","journal-title":"J Cell Physiol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adl4616","article-title":"Myeloid cell-specific loss of NPC1 in mice recapitulates microgliosis and neurodegeneration in patients with Niemann-Pick type C disease","volume":"16","author":"Dinkel","year":"2024","journal-title":"Sci Transl Med"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/15548627.2024.2440842","article-title":"Lysosomal damage due to cholesterol accumulation triggers immunogenic cell death","volume":"20","author":"Alvarez-Valadez","year":"2024","journal-title":"Autophagy"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14612","article-title":"Misrouting of v-ATPase subunit V0a1 dysregulates lysosomal acidification in a neurodegenerative lysosomal storage disease model","volume":"8","author":"Bagh","year":"2017","journal-title":"Nat Commun"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.7150\/thno.28391","article-title":"V-ATPases and osteoclasts: ambiguous future of V-ATPases inhibitors in osteoporosis","volume":"8","author":"Duan","year":"2018","journal-title":"Theranostics"}],"updated-by":[{"DOI":"10.3389\/fimmu.2025.1721889","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T00:00:00Z","timestamp":1760918400000}}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1630172\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T10:25:07Z","timestamp":1760955907000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1630172\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,19]]},"references-count":50,"alternative-id":["10.3389\/fimmu.2025.1630172"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1630172","relation":{"correction":[{"id-type":"doi","id":"10.3389\/fimmu.2025.1721889","asserted-by":"object"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,19]]},"article-number":"1630172"}}