{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T13:08:26Z","timestamp":1778504906034,"version":"3.51.4"},"reference-count":22,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jilin Province Science and Technology Development Plan Project","award":["20220204002YY"],"award-info":[{"award-number":["20220204002YY"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation, chronic airway inflammation, and immune dysregulation, and currently available therapies remain insufficient to effectively halt disease progression. In this study, we used an integrative, hypothesis-generating strategy to investigate the potential mechanisms of baicalein against COPD by combining multi-dataset transcriptomic analysis, single-cell transcriptomics, machine learning-based feature selection, Mendelian randomization (MR), molecular simulation, virtual knockout analysis, and in vitro validation. Putative targets of baicalein were predicted using CTD, SEA, and SwissTargetPrediction, and were intersected with COPD-related genes collected from GeneCards and OMIM. Four GEO datasets (GSE20257, GSE42057, GSE76925, and GSE130928) were integrated after batch-effect correction, yielding a combined cohort of 260 control samples and 250 COPD samples. Candidate genes were prioritized by intersecting the results of LASSO regression, random forest, and support vector machine. Immune-cell infiltration was estimated using CIBERSORT, and single-cell transcriptomic data were used to define the cellular localization of prioritized genes. Formal protein-level MR analysis was conducted for CD163 using deCODE plasma protein pQTL\/GWAS summary statistics as the exposure dataset and the IEU OpenGWAS COPD dataset (ebi-a-GCST90018807) as the outcome dataset. Molecular docking, molecular dynamics simulation, and virtual knockout analysis were further used to provide structural and network-level supportive evidence. Finally, LPS-stimulated BEAS-2B cells were used as an epithelial inflammatory model to evaluate the effects of baicalein by CCK-8 assay, wound-healing assay, ELISA, and RT-qPCR. Five core genes were prioritized, namely ABCC1, CD163, CYP1B1, IKBKB, and PIK3CA. Immune infiltration and single-cell analyses suggested that macrophage-associated immune regulation may represent an important mechanistic direction. MR analysis provided supportive genetic evidence for prioritizing CD163 in COPD. Molecular simulation offered preliminary structural support for several target-compound interactions. In LPS-stimulated BEAS-2B cells, baicalein reduced inflammatory cytokine release and modulated the expression of IKBKB, PIK3CA, IL1B, IL6, and IL10, thereby providing epithelial-level support for the predicted network. Taken together, these findings suggest that baicalein may exert anti-inflammatory effects in COPD through a multi-target, immune-associated mechanism, with macrophage-related regulation and CD163 emerging as noteworthy candidate directions for further investigation. This study provides an integrative framework for target prioritization and mechanistic exploration, while the predicted macrophage-centered mechanisms still require dedicated validation in immune-cell and in vivo models.<\/jats:p>","DOI":"10.3390\/molecules31101610","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T12:05:22Z","timestamp":1778501122000},"page":"1610","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-Omics Analysis and In Vitro Experimental Validation Identify Candidate Mechanisms of Baicalein Against Chronic Obstructive Pulmonary Disease"],"prefix":"10.3390","volume":"31","author":[{"given":"Yinan","family":"Liu","sequence":"first","affiliation":[{"name":"School of Pharmacy, Changchun University of Chinese Medicine, No. 1035 Boshuo Road, Jingyue National High-Tech Industrial Development Zone, Changchun 130117, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuhua","family":"Yuan","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Changchun University of Chinese Medicine, No. 1035 Boshuo Road, Jingyue National High-Tech Industrial Development Zone, Changchun 130117, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Shi","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Changchun University of Chinese Medicine, No. 1035 Boshuo Road, Jingyue National High-Tech Industrial Development Zone, Changchun 130117, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhidong","family":"Qiu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Changchun University of Chinese Medicine, No. 1035 Boshuo Road, Jingyue National High-Tech Industrial Development Zone, Changchun 130117, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuelian","family":"Dong","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Changchun University of Chinese Medicine, No. 1035 Boshuo Road, Jingyue National High-Tech Industrial Development Zone, Changchun 130117, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,11]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1164\/rccm.202009-3442OC","article-title":"Necroptosis signaling promotes inflammation, airway remodeling, and emphysema in chronic obstructive pulmonary disease","volume":"204","author":"Lu","year":"2021","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15076","DOI":"10.1038\/nrdp.2015.76","article-title":"Chronic obstructive pulmonary disease","volume":"1","author":"Barnes","year":"2015","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","unstructured":"Chinese Medical Association Respiratory Disease Society Chronic Obstructive Pulmonary Disease Group, and Chinese Physician Association Respiratory Physician Branch Chronic Obstructive Pulmonary Disease Work Committee (2021). Chronic obstructive pulmonary disease diagnosis and treatment guidelines (2021 revised version). Chin. J. Tuberc. Respir. Dis., 44, 170\u2013205."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.2147\/COPD.S366126","article-title":"Pathological mechanism and targeted drugs of COPD","volume":"17","author":"Guo","year":"2022","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2671","DOI":"10.2147\/COPD.S484664","article-title":"Analysis of COPD: Distinguishing characteristics and management of smoking vs never smoking patients","volume":"19","author":"Fekete","year":"2024","journal-title":"Int. J. Chronic Obs. Pulm. Dis."},{"key":"ref_7","first-page":"287","article-title":"Pathogenesis of chronic obstructive pulmonary disease and modulating effect of traditional Chinese medicine: A review","volume":"31","author":"Zou","year":"2025","journal-title":"Chin. J. Exp. Tradit. Med. Formulae"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Xu, J., Zeng, Q., Li, S., Su, Q., and Fan, H. (2024). Inflammation mechanism and research progress of COPD. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1404615"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6520","DOI":"10.1038\/s41467-021-26777-9","article-title":"Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease","volume":"12","author":"Hey","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Liu, Y., Kong, H., Cai, H., Chen, G., Chen, H., and Ruan, W. (2023). Progression of the PI3K\/Akt signaling pathway in chronic obstructive pulmonary disease. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1238782"},{"key":"ref_11","first-page":"1056","article-title":"An up-to-date overview of baicalein and its biological and pharmacological activities","volume":"24","author":"Yeo","year":"2025","journal-title":"EXCLI J."},{"key":"ref_12","first-page":"141","article-title":"Research progress on the chemical constituents and pharmacological effects of Scutellaria baicalensis","volume":"38","author":"Zheng","year":"2016","journal-title":"Chin. Tradit. Pat. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"102121","DOI":"10.1016\/j.pupt.2022.102121","article-title":"Mechanistic insights into the amelioration effects of lipopolysaccharide-induced acute lung injury by baicalein: An integrated systems pharmacology study and experimental validation","volume":"73\u201374","author":"Gao","year":"2022","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"He, S., Wang, S., Liu, S., Li, Z., Liu, X., and Wu, J. (2021). Baicalein Potentiated M1 Macrophage Polarization in Cancer Through Targeting PI3K\u03b3\/NF-\u03baB Signaling. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.743837"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nchembio.118","article-title":"Network pharmacology: The next paradigm in drug discovery","volume":"4","author":"Hopkins","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"ref_16","first-page":"621423","article-title":"Network pharmacology: A new approach for Chinese herbal medicine research","volume":"2013","author":"Zhang","year":"2013","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"100434","DOI":"10.1016\/j.patter.2022.100434","article-title":"scTenifoldKnk: An efficient virtual knockout tool for gene function predictions via single-cell gene regulatory network perturbation","volume":"3","author":"Osorio","year":"2022","journal-title":"Patterns"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/s41577-020-00477-9","article-title":"Regulation of immune responses by the airway epithelial cell landscape","volume":"21","author":"Hewitt","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wang, Z., Liang, W., Ma, C., Wang, J., Gao, X., and Wei, L. (2021). Macrophages Inhibit Ciliary Protein Levels by Secreting BMP-2 Leading to Airway Epithelial Remodeling Under Cigarette Smoke Exposure. Front. Mol. Biosci., 8.","DOI":"10.3389\/fmolb.2021.663987"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1111\/cts.13063","article-title":"Safety, tolerability, and pharmacokinetics of oral baicalein tablets in healthy Chinese subjects: A single-center, randomized, double-blind, placebo-controlled multiple-ascending-dose study","volume":"14","author":"Li","year":"2021","journal-title":"Clin. Transl. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"41612","DOI":"10.1038\/srep41612","article-title":"LPS-induced inflammatory response is suppressed by Wnt inhibitors, Dickkopf-1 and LGK974","volume":"7","author":"Jang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e14986","DOI":"10.7717\/peerj.14986","article-title":"LincRNA00612 inhibits apoptosis and inflammation in LPS-inducedBEAS-2B cells via enhancing interaction between p-STAT3 and A2M promoter","volume":"11","author":"Xiao","year":"2023","journal-title":"PeerJ"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/10\/1610\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T12:11:12Z","timestamp":1778501472000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/10\/1610"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,11]]},"references-count":22,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["molecules31101610"],"URL":"https:\/\/doi.org\/10.3390\/molecules31101610","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,11]]}}}