{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T03:46:04Z","timestamp":1793418364330,"version":"4.5.0"},"reference-count":128,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014717","name":"Youth Science Fund Project","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014717","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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\u2014the persistent epigenetic and metabolic reprogramming of innate immune cells\u2014underpins these paradoxes. MSU crystals and soluble urate act as dual inducers: crystals trigger acute flares via NOD\u2212, LRR\u2212 and pyrin domain\u2212containing protein 3(NLRP3) and also establish long\u2212lived myeloid memory through c\u2212Jun N\u2212terminal kinase (JNK)\u2013c\u2212Jun proto\u2212oncogene (JUN) and mechanistic target of rapamycin (mTOR)\u2013hypoxia\u2212inducible factor 1\u2212alpha (HIF-1\u03b1) 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\u2212coding RNA regulation. We discuss how trained macrophages and Th17 cells form a self\u2212amplifying 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\u2212related amplifier. Finally, we evaluate therapeutic strategies targeting epigenetic enzymes, metabolic nodes, and interleukin\u22121 beta (IL\u22121\u03b2), and highlight biomarkers and trial design needed to translate trained immunity modulation into clinical practice.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1914001","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T10:58:36Z","timestamp":1786532316000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Trained immunity in gout: epigenetic and metabolic reprogramming of innate immune memory"],"prefix":"10.3389","volume":"17","author":[{"given":"Xin","family":"Chen","sequence":"first","affiliation":[{"name":"First Clinical Medical College, Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongtong","family":"Huan","sequence":"additional","affiliation":[{"name":"Second Clinical Medical College, Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raobin","family":"Xu","sequence":"additional","affiliation":[{"name":"First Clinical Medical College, Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Fan","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieru","family":"Han","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204657","article-title":"Interactions between tenocytes and monosodium urate monohydrate crystals: implications for tendon involvement in gout","volume":"73","author":"Chhana","year":"2014","journal-title":"Ann Rheum Dis"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0036-1579709","article-title":"Dual-energy computed tomography of the knee, ankle, and foot: noninvasive diagnosis of gout and quantification of monosodium urate in tendons and ligaments","volume":"20","author":"Fritz","year":"2016","journal-title":"Semin Musculoskelet Radiol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1186\/s13075-016-1105-z","article-title":"Urate crystal deposition and bone erosion in gout: \u201cinside-out\u201d or \u201coutside-in\u201d? 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