{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T08:16:31Z","timestamp":1778573791320,"version":"3.51.4"},"reference-count":76,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:00:00Z","timestamp":1778284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Noncommunicable Chronic Diseases\u2013National Science and Technology Major Project","award":["2024ZD0522400"],"award-info":[{"award-number":["2024ZD0522400"]}]},{"name":"the China Health and Medical Development Foundation Primary Care Respiratory Clinical Research Funding Program\u2013Key Project","award":["BJ2024JCHX002"],"award-info":[{"award-number":["BJ2024JCHX002"]}]},{"name":"the ZNS Medical Foundation Clinical Research Project","award":["ZNSXS-20250069"],"award-info":[{"award-number":["ZNSXS-20250069"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic obstructive pulmonary disease (COPD) is a leading global cause of mortality. Its molecular pathogenesis, especially systemic immune dysregulation, remains unclear. Public transcriptomic datasets underwent machine learning to identify biomarkers, which were validated in external cohorts and single-cell RNA-seq. In vitro and ex vivo validations included: qRT-PCR and ELISA in CSE\/LPS-stimulated macrophages to assess drug efficacy (Celecoxib\/Lovastatin); RORC overexpression; Western blotting in patient-derived primary T cells and TCF7-deficient Jurkat cells with genetic rescue; and immunofluorescence of human lungs. A three-gene signature (RORC, TCF7, and CLEC4D) consistently discriminated COPD. CLEC4D localized to myeloid cells, while RORC\/TCF7 mapped to lymphoid lineages. Celecoxib and Lovastatin attenuated macrophage inflammation, partially via RORC preservation. Crucially, the TCF7 protein was depleted in COPD primary T cells. TCF7 knockdown downregulated pro-caspase-8, which was fully reversed by TCF7 re-expression. Immunofluorescence confirmed disrupted TCF7\/caspase-8 spatial patterns in COPD lungs. This signature highlights innate hyperactivation and adaptive T-cell alterations in COPD, providing novel mechanistic insights into immune dysregulation and potential pharmacological targets.<\/jats:p>","DOI":"10.3390\/ijms27104231","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T07:49:09Z","timestamp":1778572149000},"page":"4231","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unfolding Immune Dysregulation in COPD: Identification of a Three-Gene Signature and Functional Validation of TCF7 in Human Lung Tissue and T Lymphocytes"],"prefix":"10.3390","volume":"27","author":[{"given":"Zengrui","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Kunming Medical University, No. 1168, Chunrong West Road, Yuhua Sub-District, Chenggong District, Kunming 650500, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5213-490X","authenticated-orcid":false,"given":"Yue","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Clinical Oncology, Kunming Medical University, No. 1168, Chunrong West Road, Yuhua Sub-District, Chenggong District, Kunming 650500, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Le","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Clinical Oncology, Kunming Medical University, No. 1168, Chunrong West Road, Yuhua Sub-District, Chenggong District, Kunming 650500, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuang","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Kunming Medical University, No. 1168, Chunrong West Road, Yuhua Sub-District, Chenggong District, Kunming 650500, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,9]]},"reference":[{"key":"ref_1","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":"Celli","year":"2022","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1164\/rccm.202208-1508LE","article-title":"Chronic Obstructive Pulmonary Disease Definition: Is It Time to Incorporate the Concept of Failure of Lung Regeneration?","volume":"207","author":"Confalonieri","year":"2023","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2300806","DOI":"10.1183\/13993003.00806-2023","article-title":"From pre-COPD to COPD: A Simple, Low cost and easy to IMplement (SLIM) risk calculator","volume":"62","author":"Divo","year":"2023","journal-title":"Eur. Respir. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"Itc17","DOI":"10.7326\/AITC202008040","article-title":"Chronic Obstructive Pulmonary Disease","volume":"173","author":"Labaki","year":"2020","journal-title":"Ann. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1900164","DOI":"10.1183\/13993003.00164-2019","article-title":"Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: The GOLD science committee report 2019","volume":"53","author":"Singh","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"107850","DOI":"10.1016\/j.rmed.2024.107850","article-title":"Defining a phenotype of severe COPD patients who develop chronic hypercapnia","volume":"234","author":"Boersma","year":"2024","journal-title":"Respir. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1186\/s12931-025-03356-w","article-title":"Toward precision medicine in COPD: Phenotypes, endotypes, biomarkers, and treatable traits","volume":"26","author":"Xie","year":"2025","journal-title":"Respir. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/S2213-2600(21)00555-5","article-title":"Pathogenesis of chronic obstructive pulmonary disease: Understanding the contributions of gene-environment interactions across the lifespan","volume":"10","author":"DeMeo","year":"2022","journal-title":"Lancet Respir. Med."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Meharg, D.P., Pavlovic, S.P., Jenkins, C.R., Maguire, G.P., Jan, S., Shaw, T., Dennis, S.M., McKeough, Z., Rambaldini, B., and Gwynne, K.G. (2025). Scanning the respiratory service landscape in NSW-based Aboriginal Community Controlled Health Services. BMC Health Serv. Res., 25.","DOI":"10.1186\/s12913-025-13361-w"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.freeradbiomed.2025.09.021","article-title":"Fat mass and obesity-associated protein inhibits macrophage-mediated inflammation via the m6A demethylation of c-Jun in COPD","volume":"241","author":"Xu","year":"2025","journal-title":"Free Radic. Biol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Hong, J., Xu, Z., Xu, F., Wu, H., Liu, J., and Qu, L. (2025). Immune-related diagnostic indicators and targeted therapies for COPD combined with NASH were identified and verified via WGCNA and LASSO. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1514422"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"14347","DOI":"10.1038\/s41598-025-99002-y","article-title":"Identification and verification of mitochondria-related genes biomarkers associated with immune infiltration for COPD using WGCNA and machine learning algorithms","volume":"15","author":"Peng","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5647","DOI":"10.2147\/JIR.S438308","article-title":"A Macrophage-Related Gene Signature for Identifying COPD Based on Bioinformatics and ex vivo Experiments","volume":"16","author":"Zhang","year":"2023","journal-title":"J. Inflamm. Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Hu, C., Qian, W., Wei, R., Liu, G., Jiang, Q., Sun, Z., and Li, H. (2025). Identification of Novel Lactylation-Related Biomarkers for COPD Diagnosis Through Machine Learning and Experimental Validation. Biomedicines, 13.","DOI":"10.3390\/biomedicines13082006"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"106621","DOI":"10.1016\/j.compbiomed.2023.106621","article-title":"Revealing EXPH5 as a potential diagnostic gene biomarker of the late stage of COPD based on machine learning analysis","volume":"154","author":"Yang","year":"2023","journal-title":"Comput. Biol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Huang, Y., Niu, Y., Wang, X., Li, X., He, Y., and Liu, X. (2024). Identification of novel biomarkers related to neutrophilic inflammation in COPD. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1410158"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"34757","DOI":"10.1038\/s41598-025-18602-w","article-title":"Identification of hub genes associated with severe COPD via WGCNA and immune infiltration analysis","volume":"15","author":"Zhao","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.2147\/COPD.S511696","article-title":"Hub Genes PRPF19 and PPIB: Molecular Pathways and Potential Biomarkers in COPD","volume":"20","author":"Zhao","year":"2025","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e14","DOI":"10.1016\/S2213-2600(25)00432-1","article-title":"GOLD COPD report: 2026 update","volume":"14","author":"Venkatesan","year":"2025","journal-title":"Lancet Respir. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1016\/S2213-2600(22)00388-5","article-title":"Moving the pathway goalposts: COPD as an immune-mediated inflammatory disease","volume":"10","author":"Cass","year":"2022","journal-title":"Lancet Respir. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1016\/S0140-6736(22)00470-6","article-title":"Chronic obstructive pulmonary disease","volume":"399","author":"Christenson","year":"2022","journal-title":"Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1152\/physrev.00036.2021","article-title":"Contribution of adaptive immunity to human COPD and experimental models of emphysema","volume":"103","author":"Kheradmand","year":"2023","journal-title":"Physiol. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1164\/rccm.202107-1584OC","article-title":"Development of a Blood-based Transcriptional Risk Score for Chronic Obstructive Pulmonary Disease","volume":"205","author":"Moll","year":"2022","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1136\/thoraxjnl-2020-216401","article-title":"Blood RNA sequencing shows overlapping gene expression across COPD phenotype domains","volume":"77","author":"Ghosh","year":"2022","journal-title":"Thorax"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2100569","DOI":"10.1183\/13993003.00569-2021","article-title":"An interferon-inducible signature of airway disease from blood gene expression profiling","volume":"59","author":"Yun","year":"2022","journal-title":"Eur. Respir. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2587931","DOI":"10.1080\/07853890.2025.2587931","article-title":"Chronic obstructive pulmonary disease (COPD) and autoimmune diseases: Unravelling complex interactions","volume":"57","author":"Ceasovschih","year":"2025","journal-title":"Ann. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/s41467-022-28062-9","article-title":"Characterization of the COPD alveolar niche using single-cell RNA sequencing","volume":"13","author":"Sauler","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s12931-021-01675-2","article-title":"Single cell RNA sequencing identifies IGFBP5 and QKI as ciliated epithelial cell genes associated with severe COPD","volume":"22","author":"Li","year":"2021","journal-title":"Respir. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1186\/s12931-022-02293-2","article-title":"Single-cell transcriptomics highlights immunological dysregulations of monocytes in the pathobiology of COPD","volume":"23","author":"Huang","year":"2022","journal-title":"Respir. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1183\/09031936.05.00062304","article-title":"Phenotypic characterisation of alveolar macrophages and peripheral blood monocytes in COPD","volume":"25","author":"Pons","year":"2005","journal-title":"Eur. Respir. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2469375","DOI":"10.1080\/2162402X.2025.2469375","article-title":"Evaluating the effect of immune checkpoint inhibitor treatment on chronic obstructive pulmonary disease in lung cancer patients","volume":"14","author":"Greib","year":"2025","journal-title":"Oncoimmunology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e1381","DOI":"10.1002\/ctm2.1381","article-title":"Regulatory roles of Osteopontin in lung epithelial inflammation and epithelial-telocyte interaction","volume":"13","author":"Fu","year":"2023","journal-title":"Clin. Transl. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1186\/s12931-023-02574-4","article-title":"Role of thioredoxin in chronic obstructive pulmonary disease (COPD): A promising future target","volume":"24","author":"Kansal","year":"2023","journal-title":"Respir. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1164\/rccm.201906-1123OC","article-title":"Human Lung Conventional Dendritic Cells Orchestrate Lymphoid Neogenesis during Chronic Obstructive Pulmonary Disease","volume":"202","author":"Naessens","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"L1183","DOI":"10.1152\/ajplung.00521.2019","article-title":"The role of MIF in chronic lung diseases: Looking beyond inflammation","volume":"318","author":"Poelarends","year":"2020","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Louren\u00e7o, J.D., Ito, J.T., Martins, M.A., Tib\u00e9rio, I., and Lopes, F. (2021). Th17\/Treg Imbalance in Chronic Obstructive Pulmonary Disease: Clinical and Experimental Evidence. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.804919"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Riani Moreira, A., Uchoa da Silva, C., de Paula Costa Mattos, L., Jesus Sim\u00e3o, J., Camargo Berti, V., Henrique Vasconcelos Alves, L., Ferreira da Silva, A., Jesus Lima, F., Karoline Moreira Bezerra, S., and Nascimento Silva, C. (2025). IL-17-neutralizing antibody mitigates functional and structural changes in cigarette smoke-induced COPD model. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1641300"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"156719","DOI":"10.1016\/j.phymed.2025.156719","article-title":"Mechanisms of LouDan LiFei granule attenuate inflammatory injury in AECOPD:A network pharmacology and experimental validation","volume":"142","author":"Guo","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1016\/j.immuni.2019.09.013","article-title":"TCF-1-Centered Transcriptional Network Drives an Effector versus Exhausted CD8 T Cell-Fate Decision","volume":"51","author":"Chen","year":"2019","journal-title":"Immunity"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/s41577-021-00563-6","article-title":"TCF1 in T cell immunity: A broadened frontier","volume":"22","author":"Zhao","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/s41586-019-1770-6","article-title":"Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis","volume":"575","author":"Fritsch","year":"2019","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"103005","DOI":"10.1016\/j.cpcardiol.2025.103005","article-title":"The future of cardiology: Integrating single-cell transcriptomics with multi-omics for enhanced cardiac disease insights","volume":"50","author":"Tang","year":"2025","journal-title":"Curr. Probl. Cardiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2539","DOI":"10.2147\/COPD.S271844","article-title":"Effectiveness of Steroid Therapy on Pneumonic Chronic Obstructive Pulmonary Disease Exacerbation: A Multicenter, Retrospective Cohort Study","volume":"15","author":"Shiroshita","year":"2020","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_44","first-page":"14","article-title":"CT whole lung radiomic nomogram: A potential biomarker for lung function evaluation and identification of COPD","volume":"11","author":"Zhou","year":"2024","journal-title":"Mil. Med. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1165\/rcmb.2023-0147OC","article-title":"Epigenetic Reprogramming Drives Epithelial Disruption in Chronic Obstructive Pulmonary Disease","volume":"70","author":"Wally","year":"2024","journal-title":"Am. J. Respir. Cell. Mol. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"Jin","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1093\/ntr\/ntw129","article-title":"The Effect of Different Case Definitions of Current Smoking on the Discovery of Smoking-Related Blood Gene Expression Signatures in Chronic Obstructive Pulmonary Disease","volume":"18","author":"Obeidat","year":"2016","journal-title":"Nicotine Tob. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1165\/rcmb.2012-0230OC","article-title":"Peripheral blood mononuclear cell gene expression in chronic obstructive pulmonary disease","volume":"49","author":"Bahr","year":"2013","journal-title":"Am. J. Respir. Cell. Mol. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"791","DOI":"10.2147\/COPD.S347733","article-title":"Autophagy Induced by BCL2-Related ceRNA Network Participates in the Occurrence of COPD","volume":"17","author":"Shi","year":"2022","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Heo, Y., Kim, J., Hong, S.H., and Kim, W.J. (2025). Single cell transcriptomics in blood of patients with chronic obstructive pulmonary disease. BMC Pulm. Med., 25.","DOI":"10.1186\/s12890-024-03475-y"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Chen, K.Y., Sun, W.L., Wu, S.M., Feng, P.H., Lin, C.F., Chen, T.T., Lu, Y.H., Ho, S.C., Chen, Y.H., and Lee, K.Y. (2024). Reduced Tolerogenic Program Death-Ligand 1-Expressing Conventional Type 1 Dendritic Cells Are Associated with Rapid Decline in Chronic Obstructive Pulmonary Disease. Cells, 13.","DOI":"10.3390\/cells13100878"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Huang, S., Zhang, L., and Liu, X. (2025). Bioinformatics Approach to Identifying Molecular Targets of Isoliquiritigenin Affecting Chronic Obstructive Pulmonary Disease: A Machine Learning Pharmacology Study. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26083907"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Hu, T., Duan, X., Gao, J., Li, Z., Xu, D., Jing, J., Li, F., Ding, J., Ma, L., and Jiang, M. (2025). A comprehensive bioinformatics analysis of pathways and biomarkers shared between type 2 diabetes mellitus and chronic obstructive pulmonary disease. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1536551"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2379811","DOI":"10.1080\/15412555.2024.2379811","article-title":"Identification and Validation of Aging Related Genes Signature in Chronic Obstructive Pulmonary Disease","volume":"21","author":"Li","year":"2024","journal-title":"COPD"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"259","DOI":"10.2147\/COPD.S395492","article-title":"Analysis of Communal Molecular Mechanism Between Chronic Obstructive Pulmonary Disease and Osteoporosis","volume":"18","author":"Nie","year":"2023","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Shi, J., Wang, Z., Rao, Y., Li, D., Luo, Y., Zhang, Y., Pei, Y., Gai, X., and Sun, Y. (2025). Integrating bioinformatics and molecular experiments to reveal the critical role of the cellular energy metabolism-related marker PLA2G1B in COPD epithelial cells. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1666195"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"148711","DOI":"10.1016\/j.gene.2024.148711","article-title":"Integrated bioinformatic analysis and experimental validation for exploring the key immune checkpoint of COPD","volume":"927","author":"Ke","year":"2024","journal-title":"Gene"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2232","DOI":"10.1002\/ame2.70040","article-title":"Identification of ferroptosis-related genes involved in chronic obstructive pulmonary disease based on bioinformatics analysis","volume":"8","author":"Luan","year":"2025","journal-title":"Anim. Model. Exp. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.2147\/COPD.S354634","article-title":"Revealing lncRNA Biomarkers Related to Chronic Obstructive Pulmonary Disease Based on Bioinformatics","volume":"17","author":"Han","year":"2022","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1988","DOI":"10.1016\/S0140-6736(20)30689-9","article-title":"Clinical and biomarker changes of Alzheimer\u2019s disease in adults with Down syndrome: A cross-sectional study","volume":"395","author":"Fortea","year":"2020","journal-title":"Lancet"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1186\/s12944-023-01918-9","article-title":"Identification of key lipid metabolism-related genes in Alzheimer\u2019s disease","volume":"22","author":"Zeng","year":"2023","journal-title":"Lipids Health Dis."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3175","DOI":"10.3390\/cimb46040199","article-title":"Nur77 Mediates Anaphylaxis by Regulating miR-21a","volume":"46","author":"Jo","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1186\/gb-2008-9-s1-s4","article-title":"GeneMANIA: A real-time multiple association network integration algorithm for predicting gene function","volume":"9","author":"Mostafavi","year":"2008","journal-title":"Genome Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s12967-023-04807-y","article-title":"Integrating single-cell and bulk RNA sequencing data unveils antigen presentation and process-related CAFS and establishes a predictive signature in prostate cancer","volume":"22","author":"Wang","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Pei, G., Ma, N., Chen, F., Guo, L., Bai, J., Deng, J., and He, Z. (2021). Screening and Identification of Hub Genes in the Corticosteroid Resistance Network in Human Airway Epithelial Cells via Microarray Analysis. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.672065"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"6321","DOI":"10.2174\/0109298673326250240806051127","article-title":"A Low Expression of NRF2 Enhances Oxidative Stress and Autophagy in Myofibroblasts, Promoting Progression of Chronic Obstructive Pulmonary Disease","volume":"32","author":"Guan","year":"2025","journal-title":"Curr. Med. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e70756","DOI":"10.1096\/fj.202501120R","article-title":"Integrating Single-Cell and Experimental Analyses Uncover Macrophage Ferroptosis Is a Key Event in the Development of Chronic Obstructive Pulmonary Disease","volume":"39","author":"Duan","year":"2025","journal-title":"FASEB J."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1186\/s12967-025-06615-y","article-title":"Establishment of a prognostic model based on ER stress-related cell death genes and proposing a novel combination therapy in acute myeloid leukemia","volume":"23","author":"Wang","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1167\/iovs.67.1.46","article-title":"Digoxin Attenuates Ocular Hypertension and Protects Trabecular Meshwork Cells via Ferroptosis Inhibition","volume":"67","author":"Zhou","year":"2026","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Higashi, T., Mai, Y., Noya, Y., Horinouchi, T., Terada, K., Hoshi, A., Nepal, P., Harada, T., Horiguchi, M., and Hatate, C. (2014). A simple and rapid method for standard preparation of gas phase extract of cigarette smoke. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0107856"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Genin, M., Clement, F., Fattaccioli, A., Raes, M., and Michiels, C. (2015). M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide. BMC Cancer, 15.","DOI":"10.1186\/s12885-015-1546-9"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/0003-2697(87)90021-2","article-title":"Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction","volume":"162","author":"Chomczynski","year":"1987","journal-title":"Anal. Biochem."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Mhillaj, E., Papi, M., Paciello, F., Silvestrini, A., Rolesi, R., Palmieri, V., Perini, G., Fetoni, A.R., Trabace, L., and Mancuso, C. (2020). Celecoxib Exerts Neuroprotective Effects in \u03b2-Amyloid-Treated SH-SY5Y Cells Through the Regulation of Heme Oxygenase-1: Novel Insights for an Old Drug. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.561179"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1002\/ijc.28369","article-title":"Lovastatin-induced apoptosis is mediated by activating transcription factor 3 and enhanced in combination with salubrinal","volume":"134","author":"Niknejad","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Zaqout, S., Becker, L.L., and Kaindl, A.M. (2020). Immunofluorescence Staining of Paraffin Sections Step by Step. Front. Neuroanat., 14.","DOI":"10.3389\/fnana.2020.582218"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4231\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T07:58:37Z","timestamp":1778572717000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4231"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,9]]},"references-count":76,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27104231"],"URL":"https:\/\/doi.org\/10.3390\/ijms27104231","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,9]]}}}