Single-cell transcriptomic analysis identifies VAV3 as a critical regulator of macrophage function in gouty arthritis

Background: Gouty arthritis is a common inflammatory disease triggered by the deposition of monosodium urate (MSU)crystals in the joints, leading to both acute and chronic inflammation. While macrophages have long been implicated in the pathogenesis of gouty arthritis, the exact mechanisms, differentiation conditions, and key molecules involved remain unclear. Methods: Gene Set Enrichment Analysis (GSEA) was used to determine the primary functions of macrophages. High-dimensional weighted gene co-expression network analysis (hdWGCNA), transcription factor activity analysis, and pseudotemporal trajectory analysis were applied to identify VAV3 as a key gene regulating macrophage differentiation. The correlation between VAV3 expression and relevant biological processes was further validated through Gene Set Variation Analysis (GSVA) and by examining VAV3 expression in related bulk RNA sequencing datasets from the GEO database, confirming its association with gouty arthritis. Results: Our analysis indicates that macrophages are a crucial cell type in the synovial fluid microenvironment of gouty arthritis, where their differentiation is influenced by various factors. VAV3 is a key gene regulating macrophage differentiation and function, and its expression is positively correlated with several phenotypic features of disease progression, including angiogenesis and inflammation. The differential expression of VAV3 is validated across multiple RNA sequencing datasets from the GEO database. Conclusion: Our findings underscore the critical role of macrophages in gouty arthritis and identify VAV3 as a novel biomarker and potential therapeutic target. These results deepen our understanding of the inflammatory microenvironment in gouty arthritis and suggest that VAV3 could have broader implications in other gout-related conditions, such as gouty nephropathy.