Circulating microRNAs as Putative Causal Regulators of Peripheral Arterial Disease in Diabetic Foot: An Integrative Multi-Omics and Drug Repurposing Study
Abstract
Abstract Objective To identify causal circulating miRNAs regulating the immuno-vascular axis in DFU-associated PAD through integrative multi-omics analysis, and to map pharmacologically actionable targets via computational drug repurposing. Methods Publicly available transcriptomic datasets (GEO; n = 312 samples) were analyzed using DESeq2 for differential miRNA expression. Two-sample Mendelian randomization (MR), anchored on miRNA-QTL instruments, established causal inference. Consensus miRNA–mRNA target networks were reconstructed using miRTarBase, TargetScan, and miRDB, followed by protein–protein interaction analysis in Cytoscape. KEGG and GO enrichment were performed via clusterProfiler, and repurposing candidates were ranked through DSigDB/DGIdb with molecular docking validation in AutoDock Vina. Results Sixty-three dysregulated miRNAs were identified, of which six were causally implicated in PAD. Hub genes VEGFA, AKT1, and HIF1A anchored enriched pathways including PI3K-AKT signaling, hypoxia response, and NF-κB-mediated inflammation. Metformin, rapamycin, and atorvastatin emerged as top repurposing candidates, with docking affinities reaching − 9.8 kcal/mol. Conclusion Causal circulating miRNAs constitute a molecularly coherent regulatory layer in DFU-associated PAD, with metformin representing a biologically plausible and translationally tractable repurposing candidate for immuno-vascular restoration.
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