{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T19:02:04Z","timestamp":1785524524729,"version":"3.56.0"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005046","name":"Natural Science Foundation of Heilongjiang Province","doi-asserted-by":"publisher","award":["Grant No. PL2024H081"],"award-info":[{"award-number":["Grant No. PL2024H081"]}],"id":[{"id":"10.13039\/501100005046","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Horizontal Cooperation Project of the Second Affiliated Hospital of Harbin Medical University","award":["20220815"],"award-info":[{"award-number":["20220815"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Circadian rhythm disruption is increasingly recognized as a contributor to chronic inflammatory disorders; however, its specific significance and underlying mechanisms in chronic obstructive pulmonary disease (COPD) remain unclear. This study aimed to identify circadian rhythm-associated biomarkers in COPD and explore their diagnostic value, immune correlations, and therapeutic potential.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study integrated four lung transcriptomic datasets from the public GEO database (GSE151052, GSE38974, and GSE76925 as the discovery set, and GSE47460 as the validation set). Differentially expressed circadian rhythm\u2011related genes (DECRRGs) were identified by intersecting differentially expressed genes with circadian rhythm\u2011related genes. Functional enrichment analyses (GO and KEGG) were performed, and three machine learning algorithms were applied to screen for signature DECRRGs. An exploratory risk stratification model based on multivariate logistic regression was constructed and evaluated. Immune cell infiltration was assessed using CIBERSORT, and single-cell RNA sequencing analysis was conducted to localize the distribution of key circadian rhythm genes within specific lung cell populations. Finally, the expression of a core gene CHRNA1 was validated by qRT-PCR in peripheral blood samples from COPD patients and healthy controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified eight circadian rhythm-associated feature genes, among which CHRNA1 emerged as a consistently upregulated hub gene in COPD. An exploratory risk stratification model based on these genes exhibited good discriminatory ability in the discovery cohort (AUC\u2009=\u20090.856, 95% CI: 0.806\u20130.902). Differential expression of CHRNA1 was validated in an independent cohort and correlated significantly with pro-inflammatory immune infiltration, including increased M1 macrophages and CD8\u2009\u207a\u2009T cells. Single-cell transcriptomics further localized CHRNA1 expression predominantly within B cells in COPD lung tissue. In silico drug screening and ceRNA network analysis predicted potential therapeutics (e.g., amitriptyline, rocuronium bromide) and regulatory miRNAs\/lncRNAs. Finally, qRT-PCR confirmed a marked upregulation of CHRNA1 in peripheral blood from COPD patients (\n                      <jats:italic>*p*<\/jats:italic>\n                      \u2009&lt;\u20090.0001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings suggest that CHRNA1 may serve as a candidate circadian rhythm\u2011associated immunomodulator in COPD. It demonstrates consistent upregulation across cohorts and shows a significant association with pro\u2011inflammatory immune infiltration. Single-cell analysis revealed that CHRNA1 is predominantly expressed in pulmonary B cells. The exploratory risk stratification model and predicted therapeutic candidates highlight the translational potential of targeting circadian disruption in COPD, though prospective validation is needed before clinical application.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0353838","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T17:38:57Z","timestamp":1785519537000},"page":"e0353838","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative multi-omics and machine learning identify CHRNA1 putative circadian-immune hub in COPD"],"prefix":"10.1371","volume":"21","author":[{"given":"Lan","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiansheng","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9294-8615","authenticated-orcid":true,"given":"Jiayi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyu","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"issue":"11","key":"pone.0353838.ref001","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1164\/rccm.202204-0671PP","article-title":"Definition and nomenclature of chronic obstructive pulmonary disease: Time for its revision","volume":"206","author":"B Celli","year":"2022","journal-title":"Am J Respir Crit Care Med"},{"issue":"1","key":"pone.0353838.ref002","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s12931-024-03051-2","article-title":"Global, regional, and national burden of chronic obstructive pulmonary disease and its attributable risk factors from 1990 to 2021: an analysis for the Global Burden of Disease Study 2021","volume":"26","author":"Z Wang","year":"2025","journal-title":"Respir Res"},{"issue":"12","key":"pone.0353838.ref003","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2023.46598","article-title":"Global Burden of Chronic Obstructive Pulmonary Disease Through 2050","volume":"6","author":"E Boers","year":"2023","journal-title":"JAMA Netw Open"},{"issue":"12","key":"pone.0353838.ref004","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1016\/j.arbres.2022.04.001","article-title":"COPD in China: Current status and challenges","volume":"58","author":"Y Liang","year":"2022","journal-title":"Arch Bronconeumol"},{"key":"pone.0353838.ref005","year":"2020"},{"key":"pone.0353838.ref006","unstructured":"(GOLD) GIfCOLD. 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