International immunopharmacology · 2025
3,6'-Disinapoyl sucrose modulates GALE-mediated metabolic reprogramming to alleviate asthmatic airway inflammation.
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Jiang Haisong, Ding Ningpo, Wang Zongqi, Shang Fengxiang, Yan Guanghai, Song Yilan
Аннотация
BACKGROUND: Asthma is a heterogeneous disease characterized by chronic airway inflammation and metabolic dysregulation. Recent studies highlight the role of glycolysis and oxidative phosphorylation (OXPHOS) imbalance in asthma pathogenesis, yet the underlying molecular mechanisms remain unclear. UDP-galactose-4-epimerase (GALE), a key enzyme in galactose metabolism, has not been previously explored in asthma.
PURPOSE: This study aimed to identify asthma-associated metabolic genes and investigate the therapeutic potential of 3,6'-Disinapoyl Sucrose (DISS), a natural compound, in modulating GALE-mediated metabolic reprogramming.
RESULTS: Weighted Gene Co-Expression Network Analysis (WGCNA) of bronchial epithelial datasets (GSE43696, GSE147878, GSE143303) identified 475 asthma-associated genes enriched in carbohydrate metabolism. Intersection with glycolysis/OXPHOS hallmark genes revealed GALE as a key candidate, validated by machine learning (SVM-RFE, RF, LASSO) and multi-dataset analysis. GALE expression correlated with severe and neutrophilic asthma subtypes. Virtual screening prioritized DISS as a GALE inhibitor (-14.91 kcal/mol), which suppressed glycolysis (reduced ECAR, PFK, PKM, LDHA), restored redox balance (increased SOD/CAT, decreased MDA), and mitigated mitochondrial dysfunction (restored ΔΨm, reduced mtROS) in HDM-stimulated BEAS-2B cells. In vivo, DISS attenuated airway inflammation (reduced IL-4, IL-5, IL-13, IgE), mucus hypersecretion, and pathological remodeling in HDM-induced asthmatic mice.
CONCLUSION: GALE-driven metabolic reprogramming is a novel mechanism in asthma progression. DISS alleviates airway inflammation by targeting GALE, normalizing glycolysis, and reducing oxidative stress, offering a promising therapeutic strategy.
PURPOSE: This study aimed to identify asthma-associated metabolic genes and investigate the therapeutic potential of 3,6'-Disinapoyl Sucrose (DISS), a natural compound, in modulating GALE-mediated metabolic reprogramming.
RESULTS: Weighted Gene Co-Expression Network Analysis (WGCNA) of bronchial epithelial datasets (GSE43696, GSE147878, GSE143303) identified 475 asthma-associated genes enriched in carbohydrate metabolism. Intersection with glycolysis/OXPHOS hallmark genes revealed GALE as a key candidate, validated by machine learning (SVM-RFE, RF, LASSO) and multi-dataset analysis. GALE expression correlated with severe and neutrophilic asthma subtypes. Virtual screening prioritized DISS as a GALE inhibitor (-14.91 kcal/mol), which suppressed glycolysis (reduced ECAR, PFK, PKM, LDHA), restored redox balance (increased SOD/CAT, decreased MDA), and mitigated mitochondrial dysfunction (restored ΔΨm, reduced mtROS) in HDM-stimulated BEAS-2B cells. In vivo, DISS attenuated airway inflammation (reduced IL-4, IL-5, IL-13, IgE), mucus hypersecretion, and pathological remodeling in HDM-induced asthmatic mice.
CONCLUSION: GALE-driven metabolic reprogramming is a novel mechanism in asthma progression. DISS alleviates airway inflammation by targeting GALE, normalizing glycolysis, and reducing oxidative stress, offering a promising therapeutic strategy.