• Mendelian randomization and colocalization identified JUN as a key susceptibility gene for gout, with MAPK3 and HMGCR as closely interacting targets.
• 372 potential therapeutic compounds and 79 traditional Chinese medicines were predicted, with capsaicin and 5,6-benzoflavone showing high binding affinity to core targets.
• Capsaicin (50 μmol/L) downregulated JUN and MAPK pathway mRNA expression and reduced inflammatory cytokines in a monosodium urate-induced RAW264.7 cell model.
• Findings suggest that targeting JUN and MAPK signaling, with a treatment strategy of clearing heat and detoxifying combined with promoting blood circulation, may be promising for gout therapy.