A bioinformatics and experimental study toward new therapeutic strategies: CXCL8 in gout progression

Gout is a chronic inflammatory disease driven by hyperuricemia and recurrent immune activation. However, gout may occur in the absence of elevated serum uric acid levels, which complicates clinical diagnosis and highlights the need for reliable molecular biomarkers. The molecular mechanisms underlying gout progression remain incompletely understood. This observational study integrated bioinformatics analyses with experimental validation. Publicly available transcriptomic datasets were analyzed to identify differentially expressed genes between gout patients and healthy controls. Functional enrichment analysis, protein-protein interaction network construction, immune cell infiltration analysis, competing endogenous RNA network analysis, and gene set enrichment analysis were performed to explore C-X-C motif chemokine ligand 8 (CXCL8)-associated molecular pathways. In vitro experiments were conducted to evaluate hyperuricemia-induced inflammatory responses in renal cells. A total of 1848 differentially expressed genes were identified, which were predominantly enriched in immune and inflammatory regulatory pathways. Five hub genes were highlighted, among which CXCL8 emerged as a key mediator of immune cell activation. Gene set enrichment analysis revealed that CXCL8 was significantly associated with inflammatory signaling pathways, including the NOD-like receptor signaling pathway. Potential upstream regulators of CXCL8 were also identified. Experimental validation demonstrated that elevated uric acid levels induced renal cell injury and inflammatory responses, accompanied by increased CXCL8 expression and activation of the NOD-like receptor family pyrin domain containing 3 inflammasome pathway. This study preliminarily identifies CXCL8 as a critical inflammatory mediator involved in gout progression and suggests its potential value as a molecular biomarker and therapeutic target, providing a basis for future diagnostic and therapeutic strategies.