{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T02:03:19Z","timestamp":1789524199769,"version":"build-2803163510"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Recent studies have highlighted the critical role of 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase-3 (PFKFB3) in inflammation, with inhibitors like 3PO showing therapeutic potential in various inflammatory diseases. However, its effect on asthma inflammation remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Our study employed an integrative strategy\u2014combining network pharmacology, molecular docking, molecular dynamics simulations, and\n                      <jats:italic>in vivo<\/jats:italic>\n                      experiments\u2014to investigate 3PO\u2019s anti-inflammatory action in asthma.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Firstly, the construction of a protein-protein interaction (PPI) network identified nine hub genes: TNF, IL6, BCL2, IL1B, CASP3, RELA, MAPT, MAOB, and MAOA. Then, the KEGG pathway enrichment analysis identified the nuclear factor kappa B (NF-\u03baB) pathway as a pivotal target. Molecular docking and dynamics simulations suggested stable interactions between 3PO and key inflammatory markers, including tumor necrosis factor-\u03b1 (TNF-\u03b1), interleukin-1\u03b2 (IL-1\u03b2), interleukin-6 (IL-6), and NF-\u03baB P65. For experimental validation, the OVA-induced asthma mouse models were established. PFKFB3 expression was markedly upregulated in the lung tissues of asthmatic mice. 3PO treatment modulated mediator levels in BALF of asthmatic mice by reducing interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-13 (IL-13), interleukin-17A (IL-17A), IL-1\u03b2, TNF-\u03b1, IL-6, lactate, Immunoglobulin E (IgE), and chemokine (C-C motif) ligand 11 (CCL11), while elevating interleukin-10 (IL-10). 3PO treatment alleviated hallmark features of asthma in this model, such as airway mucus hypersecretion, goblet cell hyperplasia, and peribronchial infiltration of inflammatory cells, particularly eosinophils. Furthermore, 3PO treatment reversed key protein changes in lung tissue by increasing inhibitor of nuclear factor Kappa B-\u03b1(IKB-\u03b1) and decreasing p-NF-\u03baB P65.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These results indicate that 3PO exerts anti-inflammatory effects in asthma, and this process is associated with the suppression of the NF-\u03baB pathway, providing a novel therapeutic rationale for asthma therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1790273","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T05:23:37Z","timestamp":1775107417000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Anti-inflammatory effects of 3PO in asthmatic airway inflammation: an integrated study using network pharmacology, molecular modelling, and in vivo experiments"],"prefix":"10.3389","volume":"17","author":[{"given":"Siqing","family":"Huang","sequence":"first","affiliation":[{"name":"The Second School of Clinical Medicine, Southern Medical University","place":["Guangzhou, China"]},{"name":"Department of Pulmonary and Critical Care Medicine, The Affiliated Guangdong Second Provincial General Hospital of Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuna","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, The Affiliated Guangdong Second Provincial General Hospital of Jinan University","place":["Guangzhou, China"]},{"name":"The First Clinical Medical College, Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Gansu Provincial Hospital","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanxiong","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, The Affiliated Guangdong Second Provincial General Hospital of Jinan University","place":["Guangzhou, China"]},{"name":"Department of Pulmonary and Critical Care Medicine, The Second School of Clinical Medicine, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbih.2024.100901","article-title":"Targeting glycolysis for neuroprotection in early LPS-induced neuroinflammation","volume":"42","author":"Adriana Fernanda","year":"2024","journal-title":"Brain Behav. Immun. Health"},{"key":"B2","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1248\/bpb.b19-00892","article-title":"Multiple biological aspects of eosinophils in host defense, eosinophil-associated diseases, immunoregulation, and homeostasis: is their role beneficial, detrimental, regulator, or bystander?","volume":"43","author":"Akira","year":"2020","journal-title":"Biol. Pharm. Bull."},{"key":"B3","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1016\/s0140-6736(17)33311-1","article-title":"Asthma","volume":"391","author":"Alberto","year":"2017","journal-title":"Lancet."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-74715-4","article-title":"Molecular docking study of potential phytochemicals and their effects on the complex of SARS-CoV2 spike protein and human ACE2","volume":"10","author":"Anamika","year":"2020","journal-title":"Sci. Rep."},{"key":"B5","doi-asserted-by":"publisher","first-page":"3862","DOI":"10.1080\/07391102.2022.2058092","article-title":"Phenolic compounds as \u03b1-glucosidase inhibitors: a docking and molecular dynamics simulation study","volume":"41","author":"Ananta","year":"2022","journal-title":"J. Biomol. Struct. Dyn."},{"key":"B6","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1016\/j.ccell.2016.10.006","article-title":"Inhibition of the glycolytic activator PFKFB3 in endothelium induces tumor vessel normalization, impairs metastasis, and improves chemotherapy","volume":"30","author":"Anna Rita","year":"2016","journal-title":"Cancer Cell"},{"key":"B7","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1016\/j.tem.2019.07.010","article-title":"Antagonism between antiviral signaling and glycolysis","volume":"30","author":"Anoop Singh","year":"2019","journal-title":"Trends Endocrinol. Metab."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2394","DOI":"10.1172\/jci84144","article-title":"Current concepts of severe asthma","volume":"126","author":"Anuradha","year":"2016","journal-title":"J. Clin. Invest"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1056\/NEJM199704103361506","article-title":"Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases","volume":"336","author":"Barnes","year":"1997","journal-title":"N. Engl. J. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1056\/nejm199010113231505","article-title":"Eosinophilic inflammation in asthma","volume":"323","author":"Bousquet","year":"1990","journal-title":"N. Engl. J. Med."},{"key":"B12","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1093\/clinchem\/45.1.7","article-title":"New insights into the role of nuclear factor-kappaB, a ubiquitous transcription factor in the initiation of diseases","volume":"45","author":"Chen","year":"1999","journal-title":"Clin. Chem."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-04803-y","article-title":"IGFBP5 promotes diabetic kidney disease progression by enhancing PFKFB3-mediated endothelial glycolysis","volume":"13","author":"Chengcheng","year":"2022","journal-title":"Cell Death Dis."},{"key":"B14","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.tips.2021.11.004","article-title":"Network pharmacology: curing causal mechanisms instead of treating symptoms","volume":"43","author":"Cristian","year":"2021","journal-title":"Trends Pharmacol. Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.1002\/jcc.20291","article-title":"GROMACS: fast, flexible, and free","volume":"26","author":"David","year":"2005","journal-title":"J. Comput. Chem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1084\/jem.174.4.915","article-title":"Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression","volume":"174","author":"De Waal Malefyt","year":"1991","journal-title":"J. Exp. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"8179","DOI":"10.1111\/jcmm.15485","article-title":"Dabigatran ameliorates airway smooth muscle remodeling in asthma by modulating Yes-associated protein","volume":"24","author":"Deng","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3390\/biology12060776","article-title":"New insights into NF-\u03baB signaling in innate immunity: focus on immunometabolic crosstalks","volume":"12","author":"Dominga","year":"2023","journal-title":"Biol. (Basel)."},{"key":"B19","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1038\/nrd1549","article-title":"Docking and scoring in virtual screening for drug discovery: methods and applications","volume":"3","author":"Douglas","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"B20","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/s0378-4274(99)00024-7","article-title":"Intracellular oxidation\/reduction status in the regulation of transcription factors NF-kappaB and AP-1","volume":"106","author":"Gius","year":"1999","journal-title":"Toxicol. Lett."},{"key":"B9","article-title":"Global strategy for asthma management and prevention","year":"2025"},{"key":"B21","doi-asserted-by":"publisher","first-page":"3350","DOI":"10.1111\/febs.15327","article-title":"Glycolysis - a key player in the inflammatory response","volume":"287","author":"Gonzalo","year":"2020","journal-title":"FEBS J."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2019.103965","article-title":"MIF signaling blocking alleviates airway inflammation and airway epithelial barrier disruption in a HDM-induced asthma model","volume":"347","author":"Haibing","year":"2019","journal-title":"Cell Immunol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1016\/j.cell.2021.02.016","article-title":"The basic immunology of asthma","volume":"184","author":"Hamida","year":"2021","journal-title":"Cell"},{"key":"B24","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1038\/s41423-025-01310-w","article-title":"NF-\u03baB in inflammation and cancer","volume":"22","author":"Hongmei","year":"2025","journal-title":"Cell Mol. Immunol."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2025.101535","article-title":"Lactate facilitates pancreatic repair following acute pancreatitis by promoting reparative macrophage polarization","volume":"19","author":"Jing","year":"2025","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodchem.2024.141560","article-title":"Exploring synergistic inhibitory mechanisms of flavonoid mixtures on \u03b1-glucosidase by experimental analysis and molecular dynamics simulation","volume":"464","author":"Junkun","year":"2024","journal-title":"Food Chem."},{"key":"B27","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1159\/000346910","article-title":"Adult serum cytokine concentrations and the persistence of asthma","volume":"161","author":"Kandane-Rathnayake","year":"2013","journal-title":"Int. Arch. Allergy Immunol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1191","DOI":"10.1002\/hep.31115","article-title":"Indole alleviates diet-induced hepatic steatosis and inflammation in a manner involving myeloid cell 6-Phosphofructo-2-Kinase\/Fructose-2,6-Biphosphatase 3","volume":"72","author":"Linqiang","year":"2020","journal-title":"Hepatology"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2022.109037","article-title":"Local IL-10 replacement therapy was effective for steroid-insensitive asthma in mice","volume":"110","author":"Masaya","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2022.115781","article-title":"Iso-seco-tanapartholide from Artemisia argyi inhibits the PFKFB3-mediated glycolytic pathway to attenuate airway inflammation in lipopolysaccharide-induced acute lung injury mice","volume":"301","author":"Min","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/j.molimm.2020.09.010","article-title":"IFRD1 regulates the asthmatic responses of airway via NF-\u03baB pathway","volume":"127","author":"Ming","year":"2020","journal-title":"Mol. Immunol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1101\/sqb.2011.76.010868","article-title":"Control of glycolysis through regulation of PFK1: old friends and recent additions","volume":"76","author":"Mor","year":"2011","journal-title":"Cold Spring Harb. Symp. Quant. Biol."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2023.127380","article-title":"Exploring the inhibitory properties of biflavonoids on \u03b1-glucosidase; computational and experimental approaches","volume":"253","author":"Morteza","year":"2023","journal-title":"Int. J. Biol. Macromol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1007\/s10753-018-0880-x","article-title":"The glycolytic enzyme PFKFB3 controls TNF-\u03b1-Induced endothelial proinflammatory responses","volume":"42","author":"Ruyuan","year":"2018","journal-title":"Inflammation"},{"key":"B35","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1093\/oxfordjournals.jbchem.a021719","article-title":"Characterization of a human placental fructose-6-phosphate, 2-kinase\/fructose-2,6-bisphosphatase","volume":"122","author":"Sakakibara","year":"1997","journal-title":"J. Biochem."},{"key":"B36","doi-asserted-by":"publisher","first-page":"5341","DOI":"10.4049\/jimmunol.175.8.5341","article-title":"The eotaxin chemokines and CCR3 are fundamental regulators of allergen-induced pulmonary eosinophilia","volume":"175","author":"Samuel","year":"2005","journal-title":"J. Immunol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.3109\/02770903.2014.938353","article-title":"Serum levels of IL-10, IL-17F and IL-33 in patients with asthma: a case-control study","volume":"51","author":"Sareh","year":"2014","journal-title":"J. Asthma"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1429591","article-title":"Oleic acid attenuates asthma pathogenesis via Th1\/Th2 immune cell modulation, TLR3\/4-NF-\u03baB-related inflammation suppression, and intrinsic apoptotic pathway induction","volume":"15","author":"Soon-Young","year":"2024","journal-title":"Front. Immunol."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3390\/foods11244046","article-title":"Construction of an MLR-QSAR model based on dietary flavonoids and screening of natural \u03b1-Glucosidase inhibitors","volume":"11","author":"Ting","year":"2022","journal-title":"Foods"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1755","DOI":"10.1007\/s11427-024-2823-2","article-title":"SIRT3 deficiency reduces PFKFB3-driven T-cell glycolysis and promotes arthritic inflammation","volume":"68","author":"Ting-Ting","year":"2025","journal-title":"Sci. China Life Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"104292","DOI":"10.1016\/j.phrs.2019.104292","article-title":"Ablation of endothelial Pfkfb3 protects mice from acute lung injury in LPS-induced endotoxemia","volume":"146","author":"Wang","year":"2019","journal-title":"Pharmacol. Research"},{"key":"B42","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.taap.2019.02.007","article-title":"PFKFB3 promotes endotoxemia-induced myocardial dysfunction through inflammatory signaling and apoptotic induction","volume":"368","author":"Wen","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2023.110964","article-title":"FGF10 attenuates allergic airway inflammation in asthma by inhibiting PI3K\/AKT\/NF-\u03baB pathway","volume":"113","author":"Wenjun","year":"2023","journal-title":"Cell Signal"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1278","DOI":"10.1080\/07853890.2023.2191217","article-title":"Role of PFKFB3-driven glycolysis in sepsis","volume":"55","author":"Xiao","year":"2023","journal-title":"Ann. Medicine"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2025.114102","article-title":"PFKFB3 decreases \u03b1-ketoglutarate production while partial PFKFB3 knockdown in macrophages ameliorates arthritis in tumor necrosis factor-transgenic mice","volume":"148","author":"Xiaodong","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.placenta.2021.02.014","article-title":"PFKFB3 regulates lipopolysaccharide-induced excessive inflammation and cellular dysfunction in HTR-8\/Svneo cells: implications for the role of PFKFB3 in preeclampsia","volume":"106","author":"Yang","year":"2021","journal-title":"Placenta"},{"key":"B47","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1111\/bph.13762","article-title":"Inhibition of 6-phosphofructo-2-kinase suppresses fibroblast-like synoviocytes-mediated synovial inflammation and joint destruction in rheumatoid arthritis","volume":"174","author":"Yaoyao","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.112612","article-title":"PFKFB3 inhibitors as potential anticancer agents: mechanisms of action, current developments, and structure-activity relationships","volume":"203","author":"Yinhu","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.107334","article-title":"MiR-106a-5p targets PFKFB3 and improves sepsis through regulating macrophage pyroptosis and inflammatory response","volume":"300","author":"Yixin","year":"2024","journal-title":"J. Biol. Chem."},{"key":"B50","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1016\/j.bbrc.2017.05.173","article-title":"Blockage of glycolysis by targeting PFKFB3 alleviates sepsis-related acute lung injury via suppressing inflammation and apoptosis of alveolar epithelial cells","volume":"491","author":"Yuanqi","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.30639","article-title":"Dehydrocostus lactone ameliorates LPS-Induced acute lung injury by inhibiting PFKFB3-Mediated glycolysis","volume":"125","author":"Yue","year":"2024","journal-title":"J. Cell Biochem."},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-022-03337-3","article-title":"Study effect of probiotics and prebiotics on treatment of OVA-LPS-induced of allergic asthma inflammation and pneumonia by regulating the TLR4\/NF-kB signaling pathway","volume":"20","author":"Zhiwei","year":"2022","journal-title":"J. Transl. Med."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1790273\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T05:23:38Z","timestamp":1775107418000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1790273\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,2]]},"references-count":52,"alternative-id":["10.3389\/fphar.2026.1790273"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1790273","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,2]]},"article-number":"1790273"}}