European journal of pharmacology · 2025
Inflammation-related gene ITGA5 affects the healing of diabetic foot ulcers through PI3K-AKT signaling pathway.
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Wang Xiaoxiang, Zhang Weiqiang, Mao Lujia, Chen Jianwei, Zhou Xin, Wang Xuehua, Chen Yongjian, Zhou Sitong, Yang Ronghua
Аннотация
BACKGROUND: Diabetic foot ulcers (DFU), a severe complication of diabetes, are characterized by impaired healing due to chronic inflammation and dysregulated cellular processes. Identifying inflammation-related biomarkers and their mechanisms is critical for improving DFU management.
METHODS: Bioinformatics analysis of GEO datasets (GSE7014, GSE29221, GSE147890) identified inflammation-related differentially expressed genes (IRDEGs). Functional enrichment, LASSO regression, and SVM modeling were employed to pinpoint key genes. In vitro (HaCaT/fibroblast cultures) and in vivo (db/db mouse models) experiments validated ITGA5's role, including proliferation, migration, and PI3K-AKT pathway activation via siRNA knockdown.
RESULTS: Twelve IRDEGs were identified, with eight (CD14, IL7R, VIP, ITGA5, HBEGF, IFITM1, IRAK2, LPAR1) forming a diagnostic model (AUC >0.7). ITGA5 exhibited significant upregulation in DFU tissues and high-glucose conditions. Knockdown of ITGA5 enhanced keratinocyte/fibroblast proliferation and migration via PI3K-AKT activation. In vivo, ITGA5 silencing accelerated wound closure, improved angiogenesis, reduced pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), and increased collagen deposition.
CONCLUSION: ITGA5 drives DFU pathogenesis through suppression of PI3K-AKT signaling under hyperglycemia. Targeting ITGA5 may offer a therapeutic strategy to enhance wound healing, highlighting its potential as a diagnostic and therapeutic biomarker for DFU.
METHODS: Bioinformatics analysis of GEO datasets (GSE7014, GSE29221, GSE147890) identified inflammation-related differentially expressed genes (IRDEGs). Functional enrichment, LASSO regression, and SVM modeling were employed to pinpoint key genes. In vitro (HaCaT/fibroblast cultures) and in vivo (db/db mouse models) experiments validated ITGA5's role, including proliferation, migration, and PI3K-AKT pathway activation via siRNA knockdown.
RESULTS: Twelve IRDEGs were identified, with eight (CD14, IL7R, VIP, ITGA5, HBEGF, IFITM1, IRAK2, LPAR1) forming a diagnostic model (AUC >0.7). ITGA5 exhibited significant upregulation in DFU tissues and high-glucose conditions. Knockdown of ITGA5 enhanced keratinocyte/fibroblast proliferation and migration via PI3K-AKT activation. In vivo, ITGA5 silencing accelerated wound closure, improved angiogenesis, reduced pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), and increased collagen deposition.
CONCLUSION: ITGA5 drives DFU pathogenesis through suppression of PI3K-AKT signaling under hyperglycemia. Targeting ITGA5 may offer a therapeutic strategy to enhance wound healing, highlighting its potential as a diagnostic and therapeutic biomarker for DFU.