Trained immunity in gout: epigenetic and metabolic reprogramming of innate immune memory

Gout is a chronic inflammatory arthritis driven by monosodium urate (MSU) crystal deposition. Its global prevalence is rising steadily. Only a minority of hyperuricemic individuals develop gout, and flares often recur despite controlled serum urate, pointing to mechanisms beyond simple crystal-induced inflammation. This review synthesizes evidence that trained immunity-the persistent epigenetic and metabolic reprogramming of innate immune cells-underpins these paradoxes. MSU crystals and soluble urate act as dual inducers: crystals trigger acute flares via NOD-, LRR- and pyrin domain-containing protein 3(NLRP3) and also establish long-lived myeloid memory through c-Jun N-terminal kinase (JNK)-c-Jun proto-oncogene (JUN) and mechanistic target of rapamycin (mTOR)-hypoxia-inducible factor 1-alpha (HIF-1α) axes, while soluble urate primes cells via DNA hypomethylation and histone modifications. We detail the molecular architecture of trained immunity in gout, including central [hematopoietic stem and progenitor cells (HSPC)] and peripheral training, metabolic rewiring (glycolysis, succinate), epigenetic marks (H3K4me3, H3K27ac, DNA methylation), and non-coding RNA regulation. We discuss how trained macrophages and Th17 cells form a self-amplifying loop, and how systemic trained immunity links gout to cardiovascular disease, chronic kidney disease, and metabolic syndrome, with clonal haematopoiesis of indeterminate potential (CHIP) as an age-related amplifier. Finally, we evaluate therapeutic strategies targeting epigenetic enzymes, metabolic nodes, and interleukin-1 beta (IL-1β), and highlight biomarkers and trial design needed to translate trained immunity modulation into clinical practice.