Abstract: Objective  Arteriovenous fistula (AVF) is currently the preferred vascular pathway for hemodialysis patients, but the low maturity rate seriously affects the treatment of end-stage renal disease patients. The molecular mechanisms that affect the maturation of AVF are not fully understood yet.  Methods  The gene expression profiles of the AVF vascular tissue (GSE220796 and GSE119296) were downloaded from the Gene Expression Omnibus (GEO) database and the ferroptosis-related genes (FRGs) were obtained from the FerrDb database. We identified differentially expressed FRGs, performed functional enrichment analysis, constructed protein-protein interaction (PPI) network, and identified hub genes. Receiver operator characteristic (ROC) curve was used to analyze the diagnostic efficacy. We also investigated the potential biological mechanisms of hypoxia-inducible factor-1 alpha (HIF1A) through immune cell infiltration analysis, transcription factor prediction, and competitive endogenous RNA (ceRNA) network construction. Results  A total of 70 differentially expressed FRGs were identified (45 upregulated genes and 25 downregulated genes). Functional enrichment analysis suggested that the response to nutrient level, cell response to low oxygen level, regulation of smooth muscle cell proliferation and forkhead box protein O (FoxO) signaling pathway were involved in the processes of AVF maturation. HIF1A was one of the 10 important hub genes and up-expressed in mature AVF vascular tissue. ROC curve analysis showed that area under the curve (AUC) value of HIF1A was 0.926 for diagnosing AVF maturation. HIF1A was found to be positively correlated with activated dendritic cells (r=0.663, P=0.003) and activated mast cells (r=0.644, P=0.004) in AVF vascular tissue. Forkhead box protein M1 (FOXM1) was predicted to be a transcription factor regulating HIF1A expression, and a ceRNA network containing 71 long non-coding RNA (lncRNAs), 62 microRNAs (miRNAs), and one messenger RNA (mRNA) was successfully constructed.  Conclusion  Our study elucidates the presence of ferroptosis in vascular tissues during AVF maturation, and HIF1A is a potential biomarker for AVF maturation. This study provides a theoretical basis that HIF1A may be a therapeutic target to improve AVF maturity.

Key words: Maintenance hemodialysis, Arteriovenous fistula, Ferroptosis, Hypoxia inducible factor, Bioinformatics analysis