2. Academic Validation
  3. Gingerenone A ameliorates airway inflammation and remodeling in asthma by modulating the TLR4/MyD88/NF-κB pathway

Gingerenone A ameliorates airway inflammation and remodeling in asthma by modulating the TLR4/MyD88/NF-κB pathway

  • J Ethnopharmacol. 2025 Sep 30:120656. doi: 10.1016/j.jep.2025.120656.
Yingjie Zhu 1,  Lin Chen 2,  Jiajia Lin 2,  Miaoxiang Chen 2,  Weijing Wu 3,  Yunfeng Chen 4,  Lei Xuan 5
Affiliations

Affiliations

  • 1 Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China; Fujian Key Laboratory of Lung Stem Cells, Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, Fujian, China; Fujian Provincial Clinical Research Center of Interventional Respirology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China.
  • 2 Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China; Fujian Provincial Clinical Research Center of Interventional Respirology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China.
  • 3 Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China; Fujian Provincial Clinical Research Center of Interventional Respirology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China. Electronic address: wuweijing@fjmu.edu.cn.
  • 4 Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China; Fujian Provincial Clinical Research Center of Interventional Respirology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China. Electronic address: 9199912007@fjmu.edu.cn.
  • 5 Department of Urology, The second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China. Electronic address: xuanlei@fjmu.edu.cn.
PMID: 41038330 DOI: 10.1016/j.jep.2025.120656
Abstract

Ethnopharmacological relevance: Asthma is a disorder primarily characterized by persistent airway inflammation and structural remodeling, which involves multiple pathological changes, with epithelial-mesenchymal transition (EMT) identified as a key mechanism. Ginger is warm in nature and is associated with the lung, spleen, and stomach meridians. It has the efficacy of warming the lungs and relieving coughs, and is commonly used to treat coughs and wheezing resulting from wind-cold invading the lungs. In traditional Chinese medicine, ginger is frequently combined with Other herbs to create compound prescriptions aimed at treating respiratory diseases such as asthma. Gingerenone A (GA), a bioactive compound extracted from ginger, has been documented to possess anti-inflammatory and antioxidant activities. Notwithstanding, the effects of GA in asthma remain to be investigated.

Aim of the study: This research aimed to explore the inhibitory effects and underlying mechanisms of GA on asthmatic airway inflammation and remodeling.

Materials and methods: In vitro, cell migration was assessed via Transwell assay, and the cytotoxicity of GA was evaluated by CCK-8 assay. RT-qPCR was used to quantify inflammatory cytokine mRNA in the supernatant of MLE-12 cells stimulated with house dust Mite (HDM). The inhibitory effect of GA on NF-κB nuclear translocation was detected by immunofluorescence assay. Western blot (WB) was employed to analyze EMT-related markers, as well as key proteins in the β-catenin and TLR4 pathways, across different cell groups. Molecular docking was performed for validation; additionally, TLR4 overexpression and DARTS assay in MLE-12 cells was used to further confirm that GA regulates EMT and β-catenin in a TLR4-dependent manner. In vivo, Hematoxylin and eosin (H&E), Masson's trichrome, and periodic acid-Schiff (PAS) staining were applied to evaluate the extent of pathological changes in lung tissues. WB, immunofluorescence (IF), and immunohistochemistry (IHC) were used to assess key proteins in the β-catenin and TLR4 pathways within lung tissues.

Results: Results showed that GA suppressed HDM-induced secretion of inflammatory factors in MLE-12 cells (e.g., IL-1β: 296.4 ± 34.93 vs. 38.58 ± 14.38 pg/mL, P < 0.05) and alleviated HDM-induced EMT. In asthmatic mice, GA inhibited airway inflammatory cell aggregation, cytokine secretion, and EMT-characterized airway remodeling; this effect was mediated by suppressing nuclear β-catenin. Molecular docking revealed GA bound to TLR4, MyD88, and TRAF6 with binding energies of -6.1, -5.9, and -5.5 kcal/mol, respectively. Western blot indicated GA significantly inhibited the TLR4 pathway in vitro and in vivo, with 20 mg/kg GA showing more pronounced suppression of key proteins (e.g., TLR4, p-NF-κB) than 10 mg/kg. In TLR4-overexpressing MLE-12 cells, GA's anti-inflammatory and EMT-suppressive effects were reversed. Additionally, the DARTS assay showed GA enhanced TLR4 stability against proteases.

Conclusion: This study first elucidates that GA inhibits inflammation and EMT, thereby reducing airway remodeling via inhibition of the TLR4/MyD88/NF-κB signaling cascade in asthma. These findings offer a theoretical foundation for the use of GA as a treatment for asthma and offer a potential new therapeutic approach for the condition.

Keywords

Airway remodeling; Asthma; Epithelial-mesenchymal transition; Gingerenone A; Natural compounds.

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