{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:52:31Z","timestamp":1761094351733,"version":"build-2065373602"},"reference-count":49,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Chronic obstructive pulmonary disease (COPD), multiple sclerosis (MS), and lung cancer are linked by shared inflammatory pathways and immune dysregulation. miRNAs regulate these processes by influencing gene expression, yet their roles in the molecular mechanisms across neurological and respiratory systems are not fully understood.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>This study aims to identify miRNAs and their target genes regulating inflammatory pathways, advancing the understanding of molecular genetics underlying COPD, MS, and lung cancer.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>miRNA expression data (GSE61741) were analyzed using a Random Forest (RF) model optimized via Grid Search and validated with Stratified K-Fold cross-validation. Synthetic Minority Oversampling (SMOTE) addressed data imbalance, while SHapley Additive exPlanations (SHAP) identified key miRNAs. Functional enrichment and pathway analyses explored miRNA-gene interactions. Single-cell level analysis further validated the cell-specific roles of these genes. An independent dataset (GSE31568) was used for validation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Key miRNAs, including hsa-let-7c, hsa-miR-454, hsa-miR-92a, and hsa-miR-223, were identified as regulators of hallmark inflammatory genes such as CCL2, IL6, ITGB3, and MYC. These genes are critical for cytokine signaling, epithelial repair, and immune modulation. Single-cell analysis highlighted the role of inflammatory fibroblasts in localized inflammation and tissue remodeling. The RF model achieved an accuracy of 81.58%, validated at 82.55%. Pathway analysis emphasized cytokine-cytokine receptor interactions and shared pathways between neurological and respiratory diseases.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This study identifies miRNAs and their target genes as critical regulators of inflammation in COPD, MS, and lung cancer. Single-cell insights and pathway enrichment provide a comprehensive view of shared molecular mechanisms, contributing to biomarker discovery and therapeutic strategies for precision medicine in inflammatory diseases.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/intbio\/zyaf020","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T16:38:26Z","timestamp":1761064706000},"source":"Crossref","is-referenced-by-count":0,"title":["Explicating miRNA-mediated regulation of inflammatory pathways in COPD, MS, and lung cancer using explainable artificial intelligence: insights from peripheral blood profiles"],"prefix":"10.1093","volume":"17","author":[{"given":"Nakul","family":"Tanwar","sequence":"first","affiliation":[{"name":"Department of Biotechnology, Delhi Technological University Shahbad Daulatpur , Main Bawana Road, Delhi-110042 ,","place":["India"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0116-0711","authenticated-orcid":false,"given":"Yasha","family":"Hasija","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Delhi Technological University Shahbad Daulatpur , Main Bawana Road, Delhi-110042 ,","place":["India"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"2025102112382440400_ref1","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1016\/j.rmed.2015.01.018","article-title":"Respiratory dysfunction in multiple sclerosis","volume":"109","author":"Tzelepis","year":"2015","journal-title":"Respir Med"},{"key":"2025102112382440400_ref2","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1007\/s00408-008-9081-y","article-title":"Increased prevalence of multiple sclerosis among COPD patients and their first-degree relatives: a population-based study","volume":"186","author":"Egesten","year":"2008","journal-title":"Lung"},{"key":"2025102112382440400_ref3","doi-asserted-by":"publisher","first-page":"102927","DOI":"10.1016\/j.msard.2021.102927","article-title":"Lung cancer risk in patients with multiple sclerosis: a Mendelian randomization analysis","volume":"51","author":"Ge","year":"2021","journal-title":"Mult Scler Relat Disord"},{"key":"2025102112382440400_ref4","doi-asserted-by":"publisher","DOI":"10.1177\/17562864211007687","article-title":"Inflammation in multiple sclerosis","volume":"14","author":"Haase","year":"2021","journal-title":"Ther Adv Neurol Disord"},{"key":"2025102112382440400_ref5","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/j.coph.2009.06.009","article-title":"Current concepts on the role of inflammation in COPD and lung cancer","volume":"9","author":"Yao","year":"2009","journal-title":"Curr Opin Pharmacol"},{"key":"2025102112382440400_ref6","doi-asserted-by":"publisher","first-page":"15479","DOI":"10.3390\/ijms232415479","article-title":"The role of microRNAs in inflammation","volume":"23","author":"Das","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2025102112382440400_ref7","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1186\/S12916-014-0224-0","article-title":"miRNAs can be generally associated with human pathologies as exemplified for miR-144","volume":"12","author":"Keller","year":"2014","journal-title":"BMC Med"},{"key":"2025102112382440400_ref8","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1038\/nmeth.1682","article-title":"Toward the blood-borne miRNome of human diseases","volume":"8","author":"Keller","year":"2011","journal-title":"Nat Methods"},{"key":"2025102112382440400_ref9","doi-asserted-by":"crossref","first-page":"24039","DOI":"10.1038\/s41598-021-03430-5","article-title":"Research on expansion and classification of imbalanced data based on SMOTE algorithm","volume":"11","author":"Wang","year":"2021","journal-title":"Sci Rep"},{"key":"2025102112382440400_ref10","doi-asserted-by":"publisher","first-page":"105505","DOI":"10.1016\/j.compbiomed.2022.105505","article-title":"Application of explainable artificial intelligence in the identification of squamous cell carcinoma biomarkers","volume":"146","author":"Meena","year":"2022","journal-title":"Comput Biol Med"},{"key":"2025102112382440400_ref11","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1186\/s12859-018-2486-6","article-title":"iDEP: an integrated web application for differential expression and pathway analysis of RNA-Seq data","volume":"19","author":"Ge","year":"2018","journal-title":"BMC Bioinformatics"},{"key":"2025102112382440400_ref12","doi-asserted-by":"publisher","first-page":"2557","DOI":"10.1007\/s11517-024-03099-8","article-title":"Hasija Y (2024) explicate molecular landscape of combined pulmonary fibrosis and emphysema through explainable artificial intelligence: a comprehensive analysis of ILD and COPD interactions using RNA from whole lung homogenates","volume":"62","author":"Tanwar","year":"2024","journal-title":"Med Biol Eng Comput"},{"key":"2025102112382440400_ref13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12859-019-3105-x","article-title":"MIENTURNET: an interactive web tool for microRNA-target enrichment and network-based analysis","volume":"20","author":"Licursi","year":"2019","journal-title":"BMC Bioinformatics"},{"key":"2025102112382440400_ref14","doi-asserted-by":"publisher","first-page":"e0294236","DOI":"10.1371\/journal.pone.0294236","article-title":"SRplot: a free online platform for data visualization and graphing","volume":"18","author":"Tang","year":"2023","journal-title":"PloS One"},{"key":"2025102112382440400_ref15","doi-asserted-by":"publisher","article-title":"Single Cell Portal: an interactive home for single-cell genomics data","author":"","DOI":"10.1101\/2023.07.13.548886"},{"key":"2025102112382440400_ref16","doi-asserted-by":"publisher","first-page":"104979","DOI":"10.1016\/j.bspc.2023.104979","article-title":"XAI-CNVMarker: explainable AI-based copy number variant biomarker discovery for breast cancer subtypes","volume":"84","author":"Rajpal","year":"2023","journal-title":"Biomed Signal Process Control"},{"key":"2025102112382440400_ref17","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1002\/path.5399","article-title":"MicroRNAs in gray and white matter multiple sclerosis lesions: impact on pathophysiology","volume":"250","author":"Teuber-Hanselmann","year":"2020","journal-title":"J Pathol"},{"key":"2025102112382440400_ref18","doi-asserted-by":"publisher","first-page":"578531","DOI":"10.1016\/j.jneuroim.2025.578531","article-title":"MicroRNA signatures of CD4+ T cell subsets in healthy and multiple sclerosis subjects determined by small RNA-sequencing","volume":"401","author":"Culina","year":"2025","journal-title":"J Neuroimmunol"},{"key":"2025102112382440400_ref19","doi-asserted-by":"publisher","first-page":"e491","DOI":"10.1212\/NXI.0000000000000491","article-title":"Identification of MS-specific serum miRNAs in an international multicenter study","volume":"5","author":"Regev","year":"2018","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"2025102112382440400_ref20","doi-asserted-by":"crossref","first-page":"330","DOI":"10.3390\/cells10020330","article-title":"The microRNA let-7b-5p is negatively associated with inflammation and disease severity in multiple sclerosis","volume":"10","author":"Mandolesi","year":"2021","journal-title":"Cells"},{"key":"2025102112382440400_ref21","doi-asserted-by":"publisher","first-page":"575","DOI":"10.2147\/COPD.S404850","article-title":"MicroRNA Let-7 induces M2 macrophage polarization in COPD emphysema through the IL-6\/STAT3 pathway","volume":"18","author":"Liu","year":"2023","journal-title":"Int J COPD"},{"key":"2025102112382440400_ref22","doi-asserted-by":"publisher","first-page":"e13425","DOI":"10.1111\/eci.13425","article-title":"Let-7 mediated airway remodelling in chronic obstructive pulmonary disease via the regulation of IL-6","volume":"51","author":"Di","year":"2021","journal-title":"Eur J Clin Invest"},{"key":"2025102112382440400_ref23","doi-asserted-by":"publisher","first-page":"643942","DOI":"10.3389\/fcell.2021.643942","article-title":"Frontiers of MicroRNA signature in non-small cell lung cancer","volume":"9","author":"Zhu","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"2025102112382440400_ref24","doi-asserted-by":"publisher","first-page":"810","DOI":"10.7150\/ijms.8647","article-title":"Expression, regulation and function of MicroRNAs in multiple sclerosis","volume":"11","author":"Ma","year":"2014","journal-title":"Int J Med Sci"},{"key":"2025102112382440400_ref25","doi-asserted-by":"publisher","first-page":"995","DOI":"10.3390\/toxics11120995","article-title":"Exploration of the pathogenesis of chronic obstructive pulmonary disease caused by smoking\u2014based on bioinformatics analysis and In vitro experimental evidence","volume":"11","author":"Zhang","year":"2023","journal-title":"Toxics"},{"key":"2025102112382440400_ref26","doi-asserted-by":"publisher","first-page":"104839","DOI":"10.1016\/j.msard.2023.104839","article-title":"Targeting miR-223 enhances myeloid-derived suppressor cell suppressive activities in multiple sclerosis patients","volume":"76","author":"Cantoni","year":"2023","journal-title":"Mult Scler Relat Disord"},{"key":"2025102112382440400_ref27","doi-asserted-by":"publisher","first-page":"196","DOI":"10.3389\/fmed.2020.00196","article-title":"miR-223: a key regulator in the innate immune response in asthma and COPD","volume":"7","author":"Roffel","year":"2020","journal-title":"Front Med (Lausanne)"},{"key":"2025102112382440400_ref28","doi-asserted-by":"publisher","DOI":"10.1172\/JCI155693","article-title":"microRNA-92a promotes CNS autoimmunity by modulating the regulatory and inflammatory T cell balance","volume":"132","author":"","journal-title":"J Clin Invest"},{"key":"2025102112382440400_ref29","doi-asserted-by":"publisher","first-page":"748356","DOI":"10.3389\/fgene.2021.748356","article-title":"Identifying miRNA-mRNA networks associated with COPD phenotypes","volume":"12","author":"Zhuang","year":"2021","journal-title":"Front Genet"},{"key":"2025102112382440400_ref30","doi-asserted-by":"publisher","DOI":"10.1109\/I4Tech55392.2022.9952865","article-title":"Explicate toxicity by explainable artificial intelligence","volume-title":"2022 International Conference on Industry 4.0 Technology (I4Tech)","author":""},{"key":"2025102112382440400_ref31","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":"2025102112382440400_ref32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12964-024-01746-z","article-title":"Targeting CCL2-CCR2 signaling pathway alleviates macrophage dysfunction in COPD via PI3K-AKT axis","volume":"22","author":"Dong","year":"2024","journal-title":"Cell Commun Signal"},{"key":"2025102112382440400_ref33","doi-asserted-by":"publisher","first-page":"e13115","DOI":"10.1111\/cpr.13115","article-title":"Role of the CCL2-CCR2 signalling axis in cancer: mechanisms and therapeutic targeting","volume":"54","author":"Xu","year":"2021","journal-title":"Cell Prolif"},{"key":"2025102112382440400_ref34","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.cytogfr.2020.12.005","article-title":"The cytokine storm in COVID-19: further advances in our understanding the role of specific chemokines involved","volume":"58","author":"Coperchini","year":"2021","journal-title":"Cytokine Growth Factor Rev"},{"key":"2025102112382440400_ref35","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.gendis.2021.08.004","article-title":"CCL5\/CCR5 axis in human diseases and related treatments","volume":"9","author":"Zeng","year":"2022","journal-title":"Genes Dis"},{"key":"2025102112382440400_ref36","doi-asserted-by":"publisher","first-page":"105174","DOI":"10.1016\/j.msard.2023.105174","article-title":"The role of chemokines (CCL2, CCL5 and CXCL10) in the Neuroinflammation among patients with multiple sclerosis","volume":"80","author":"Salim","year":"2023","journal-title":"Mult Scler Relat Disord"},{"key":"2025102112382440400_ref37","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1016\/j.cyto.2015.01.009","article-title":"Seeking balance: potentiation and inhibition of multiple sclerosis autoimmune responses by IL-6 and IL-10","volume":"73","author":"Ireland","year":"2015","journal-title":"Cytokine"},{"key":"2025102112382440400_ref38","doi-asserted-by":"publisher","DOI":"10.1177\/1721727X221149534","article-title":"Pulmonary infection is associated with an increased IL-6 in acute exacerbation chronic obstructive pulmonary disease","volume":"21","author":"Tang","year":"2023","journal-title":"Eur J Inflamm"},{"key":"2025102112382440400_ref39","doi-asserted-by":"publisher","first-page":"3209","DOI":"10.1158\/0008-5472.CAN-14-3042","article-title":"Interleukin-6 prevents the initiation but enhances the progression of lung cancer","volume":"75","author":"Qu","year":"2015","journal-title":"Cancer Res"},{"key":"2025102112382440400_ref40","first-page":"7195","article-title":"ITGB3\/CD61: a hub modulator and target in the tumor microenvironment","volume":"11","author":"Zhu","year":"2019","journal-title":"Am J Transl Res"},{"key":"2025102112382440400_ref41","article-title":"Cajal S (2020) ITGB3-mediated uptake of small extracellular vesicles facilitates intercellular communication in breast cancer cells","volume":"11","author":"Fuentes","journal-title":"Nat Commun"},{"key":"2025102112382440400_ref42","doi-asserted-by":"publisher","first-page":"2763","DOI":"10.3390\/cells10102763","article-title":"The role of epithelial damage in the pulmonary immune response","volume":"10","author":"Burgoyne","year":"2021","journal-title":"Cells"},{"key":"2025102112382440400_ref43","doi-asserted-by":"publisher","first-page":"620963","DOI":"10.3389\/fimmu.2021.620963","article-title":"Platelets in multiple sclerosis: early and central mediators of inflammation and neurodegeneration and attractive targets for molecular imaging and site-directed therapy","volume":"12","author":"Orian","year":"2021","journal-title":"Front Immunol"},{"key":"2025102112382440400_ref44","doi-asserted-by":"publisher","first-page":"103479","DOI":"10.1016\/j.ebiom.2021.103479","article-title":"A new cytokine target for chronic obstructive pulmonary disease?","volume":"69","author":"Bernhagen","year":"2021","journal-title":"E Bio Med"},{"key":"2025102112382440400_ref45","doi-asserted-by":"publisher","first-page":"L1091","DOI":"10.1152\/ajplung.00252.2021","article-title":"MiR-223 is increased in lungs of patients with COPD and modulates cigarette smoke-induced pulmonary inflammation","volume":"321","author":"Roffel","year":"2021","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2025102112382440400_ref46","doi-asserted-by":"publisher","first-page":"1015835","DOI":"10.3389\/fphar.2022.1015835","article-title":"The neuroprotective effects of fisetin, a natural flavonoid in neurodegenerative diseases: focus on the role of oxidative stress","volume":"13","author":"Hassan","year":"2022","journal-title":"Front Pharmacol"},{"key":"2025102112382440400_ref47","first-page":"1","article-title":"Silymarin attenuates cigarette smoke extract-induced inflammation via simultaneous inhibition of autophagy and ERK\/p38 MAPK pathway in human bronchial epithelial cells","volume":"6","author":"Li","year":"2016","journal-title":"Sci Rep"},{"key":"2025102112382440400_ref48","doi-asserted-by":"publisher","first-page":"1919","DOI":"10.1038\/S41467-023-37633-3","article-title":"Signalling inhibition by ponatinib disrupts productive alternative lengthening of telomeres (ALT)","volume":"14","author":"Kusuma","year":"2023","journal-title":"Nat Commun"},{"key":"2025102112382440400_ref49","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/s41392-025-02180-4","article-title":"Targeting PI3K inhibitor resistance in breast cancer with metabolic drugs","volume":"10","author":"Gremke","year":"2025","journal-title":"Signal Transduct Target Ther"}],"container-title":["Integrative Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ib\/article-pdf\/doi\/10.1093\/intbio\/zyaf020\/64830981\/zyaf020.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ib\/article-pdf\/doi\/10.1093\/intbio\/zyaf020\/64830981\/zyaf020.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T16:38:27Z","timestamp":1761064707000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ib\/article\/doi\/10.1093\/intbio\/zyaf020\/8294282"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025]]},"references-count":49,"URL":"https:\/\/doi.org\/10.1093\/intbio\/zyaf020","relation":{},"ISSN":["1757-9708"],"issn-type":[{"value":"1757-9708","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025]]},"published":{"date-parts":[[2025]]},"article-number":"zyaf020"}}