To explore the potential effects and mechanisms of Benincasae Exocarpium on arteriovenous fistula maturation based on network pharmacology and bioinformatics.

The AVF vascular tissue gene expression datasets GSE220796 and GSE119296 were downloaded from the Gene Expression Omnibus (GEO). The inflammation response-related gene sets were obtained from the Molecular Signatures Database (MSigDB) matched with the Gene Set Enrichment Analysis (GSEA) software, and differentially expressed inflammation-related genes (DE-IRGs) were screened. Pathway enrichment analysis was conducted via the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). A protein-protein interaction (PPI) network was constructed, and hub genes of the network were screened using seven topological algorithms built into plugins of the bioinformatics visualization software Cytoscape. Chemical constituents contained in Benincasae Exocarpium were retrieved via the High-throughput Experiment- and Reference-guided database of traditional Chinese medicine (HERB) and the Symptom Mapping database (SymMap). The SwissTargetPrediction database was adopted to predict potential target genes corresponding to the active ingredients of Benincasae Exocarpium. The target genes of active ingredients from Benincasae Exocarpium and core genes associated with AVF were screened out, and cavity-detection-guided blind docking software version 2 (CB-DOCK2) was used for molecular docking verification.

A total of 44 DE-IRGs associated with AVF maturation were identified, being mainly enriched in biological processes such as cellular response to bacterial molecules, leukocyte-cell adhesion, and cellular response to biological stimuli, as well as the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway and the tumor necrosis factor (TNF) signaling pathway. PPI network analysis identified hub genes as IL10, SELL, ICAM1, CXCL9, CD69, CCL2, LIF, CXCL8, CCRL2, and IL6, while 14 active chemical constituents of Benincasae Exocarpium were screened out. The SwissTargetPrediction tool was used to predict 448 potential target genes, and the intersection of these target genes and DE-IRGs yielded 5 shared genes as PDE4B, ICAM1, CCL2, HIF1A and NFKBIA. The molecular docking results showed that the binding energies of uralenol and licoflavonol A with HIF1A were -7.8 kcal/mol and -6.9 kcal/mol, respectively. The binding energies of ferulic acid and licoricone with PDE4B were -7.4 kcal/mol and -10.1 kcal/mol, respectively. And the binding energy of uralenin with CCL2 was -8.4 kcal/mol.

Benincasae Exocarpium may promote the maturation of AVF through pathways such as targeted regulation of inflammation genes related to AVF maturation, inhibition of inflammatory responses, and mediation of vascular remodeling.