Finally, these lysosomal, ER-stress, electrolyte and microbiome insults converge on an NLRP3-dependent IL-1/IL-18 surge coupled to IL-6/STAT3 trans-activation—the canonical cytokine axis driving systemic JIA flares—thus providing a coherent molecular rationale for our multi-omics evidence that implicates lansoprazole as a plausible pharmacological trigger of sJIA-like inflammation in genetically susceptible children. This evidence concerns the gene IL18 and juvenile idiopathic arthritis.