Targeting innate immune memory: a new paradigm for gout treatment

Gout is a chronic inflammatory arthritis driven by monosodium urate crystal deposition and the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation, leading to interleukin-1β (IL-1β)-mediated inflammation. Recent studies reveal that hyperuricemia induces a state of immunological memory in innate immune cells through persistent epigenetic and metabolic reprogramming of monocytes and macrophages. These alterations enhance the responsiveness of innate immune cells, leading to exaggerated inflammatory reactions upon subsequent stimulation. This review synthesizes recent studies that elucidate how metabolic shifts (e.g., increased glycolysis and fumarate accumulation) and epigenetic changes (e.g., altered histone methylation and DNA methylation) reinforce this pathogenic memory. Importantly, these mechanistic insights provide the rationale for emerging therapeutic strategies: IL-1β inhibitors aim to interrupt the central inflammatory axis; metabolic modulators (e.g., metformin, statins) seek to reverse the trained metabolic state; and epigenetic therapies [e.g., histone deacetylase (HDAC) or DNA methyltransferase (DNMT) inhibitors] hold potential to reset dysregulated immune programming. Collectively, this review argues that multi-layered intervention, such as cytokine blockade for acute control, coupled with metabolic or epigenetic remodeling for long-term reprogramming, could yield sustained disease suppression and reduced flare frequency in gout.