Identification of 2-Deoxy-D-Glucose for Chronic Eczema by Connectivity Map Analysis Followed by Animal Validation
Year: 2025
Type: article
Abstract: Objective: Chronic eczema (CE) features dry, itchy skin, while its pathogenesis remains unclear. This study was aimed to identify key genes and potential prospective drugs for CE pathogenesis. Methods: This was a combined bioinformatics prediction and experimental validation study. Clinical microarray dataset GSE63741 from Gene Expression Omnibus database was chosen to identify differentially expressed genes (DEGs) in CE. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes and Gene set enrichment analysis were conducted to explore the functional enrichment and associated pathways of the DEGs, and a protein–protein interactions network was built using STRING database. Connectivity Map analyses were carried out to identify candidate compounds. CE model mice were induced by dinitrochlorobenzene for therapeutic evaluation. The tissue levels of interleukin (IL) -4 and tumor necrosis factor (TNF)-α in mice ears and the serum levels of TNF-α, IL-4, IL-6, and interferon (IFN)-γ were assessed by immunohistochemistry, respectively. Western blotting was employed to assay the enolase 2 and hexokinase II expression. One-way analysis of variance revealed significant differences among groups, followed by Tukey’s post hoc test for pairwise comparisons. Results: A total of 94 DEGs were identified, comprising 48 upregulated genes and 46 downregulated genes. The Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the DEGs were primarily influenced by the IL-17, Staphylococcus aureus infection, and estrogen signaling pathway. The protein–protein interactions network consisted 79 nodes and 586 edges, with 30 genes identified as hub genes. In the Gene set enrichment analysis analyses, the DEGs were predominantly involved in signaling pathways related to IL-2, IL-6, IFN-γ, and IFN-α. The Connectivity Map analyses identified 2-deoxy- D -glucose (2-DG) as a potential therapeutic agent for CE. In the therapeutic evaluation, the 2-DG-treated mice exhibited significantly reduced epidermal thickness, inflammatory cell infiltration, and right ear weight compared with the model mice, with dose dependence. Moreover, 2-DG exerted anti-inflammatory effects by inhibiting the expression of pro-inflammatory cytokines TNF-α, IL-6, IFN-γ (model vs. 4% 2-DG treatment, TNF-α, 1,208.04 ± 39.92 ng/L vs. 1,040.44 ± 36.92 ng/L; IL-6, 179.81 ± 7.13 pg/mL vs. 153.44 ± 5.95 pg/mL; IFN-γ, 1,225.58 ± 52.72 ng/L vs. 1,028.29 ± 55.23 ng/L, all P < 0.001) and increasing the expression levels of IL-4 in both the ear tissue and serum (model vs. 4% 2-DG treatment, 135.45 ± 12.21 pg/mL vs. 227.42 ± 8.44 pg/mL, P < 0.001). 2-DG also reduced the protein expressions of Enolase 2 (model vs. 4% 2-DG treatment, 1.55 ± 0.02 vs. 0.99 ± 0.16, P < 0.001) in the ear tissue. Conclusions: This study revealed the key gene networks and core pathways of CE through bioinformatics analysis and verified that the glycolytic inhibitor 2-DG significantly alleviated CE symptoms by regulating the expression of inflammatory factors and metabolic enzymes in mice models, providing a basis for further in-depth understanding of the pathogenesis of CE and the development of treatment strategies.
Authors: Li-Lan Luo, Jian-Jun Gong, Kun Cao, Wan-Lu Zhao, Teng-Jian Wang, Yue Wu, Zhe-Yuan Lin, Qing-Shan Ma, Lin-Kun Tian, Lu-Ping Qin, Quan-Long Zhang
Language: English
Subfield: Dermatology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W4416594392