Multi-omics Profiling Identifies Enrichment of RIG-I Associated Inflammation and HIF-1α Related Signaling in Arteriovenous Fistula Failure

Background Autologous arteriovenous fistula (AVF) is the preferred vascular access for maintenance hemodialysis; however, long-term patency is frequently limited by stenosis and thrombosis. The molecular features distinguishing successful AVF maturation from failure remain incompletely defined. This study applied a multi-omics approach to characterize inflammatory, hypoxia-associated, and metabolic signatures in human AVF tissues. Methods Paired vascular specimens were collected from the same individuals at the time of AVF creation and at subsequent reoperation, enabling subject-level comparison between baseline (Pre-S or Pre-F) and postoperative (Po-S or Po-F) states. Bulk RNA sequencing was performed to identify differentially expressed genes and enriched signaling pathways using paired analytical models. Proteomic profiling was performed using a non-paired group-based design on Pre-AVF, Po-S, and Po-F specimens to characterize differential protein expression and associated metabolic alterations. Results Comparative transcriptomic analysis identified 463 differentially expressed genes (DEGs) in Po-S vs Pre-S, 833 DEGs in Po-F vs Pre-F, and 1,221 DEGs in Po-F vs Po-S. Relative to Po-S, Po-F specimens demonstrated enrichment of innate immune and inflammatory signaling pathways, including RIG-I–like receptor signaling, TNF/NF-κB cascades, IL-17 signaling, necroptosis, neutrophil extracellular trap formation, and oxidative stress–related processes. KEGG pathway analysis further revealed significant enrichment of hypoxia-associated pathways, including HIF-1 signaling, in Po-F tissues. In contrast, Po-S samples exhibited comparatively lower enrichment of inflammatory and hypoxia-related gene signatures. Proteomic profiling identified 111 differentially expressed proteins between Po-F and Po-S specimens. Functional annotation analysis indicated reduced representation of proteins involved in tricarboxylic acid (TCA) cycle and pyruvate metabolism, alongside increased representation of glycolysis-associated and metal-ion–binding proteins in Po-F tissues, consistent with altered metabolic pathway enrichment. Conclusion AVF failure is associated with heightened inflammatory pathway enrichment, including RIG-I–related innate immune signatures, increased representation of hypoxia-associated transcriptional programs, and metabolic alterations characterized by reduced oxidative metabolism and increased glycolytic signatures. In contrast, successful AVF maturation is accompanied by comparatively attenuated inflammatory and hypoxic pathway enrichment. These findings delineate a multi-layered molecular landscape linking innate immune signaling, hypoxia-associated remodeling, and metabolic pathway alterations in human AVF tissues and provide a framework for future mechanistic and therapeutic investigation.