{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T19:48:03Z","timestamp":1793908083955,"version":"4.8.0"},"reference-count":200,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Tophus is a hallmark lesion of chronic gout, formed through the combined effects of monosodium urate (MSU) crystal deposition, persistent inflammation, and progressive tissue fibrosis. These lesions can cause joint deformities, functional impairment, and renal damage, resulting in a significant decline in patients\u2019 quality of life. Although hyperuricemia has traditionally been regarded as the primary cause of tophus formation, this explanation does not fully account for the considerable clinical heterogeneity observed among patients. In this study, we describe the multistage and dynamic pathological process underlying tophus formation. Building upon the foundation of hyperuricemia, the study focuses on MSU crystal nucleation, growth, and aggregation; crystal-triggered innate immune activation and NLRP3 inflammasome-mediated inflammatory cascades; the dual roles of neutrophil infiltration and neutrophil extracellular traps; macrophage phenotypic conversion, fibroblast activation, and extracellular matrix remodeling; the formation of multinucleated giant cells, complex cellular infiltration, and pathological angiogenesis; and the final formation of a mature, dense fibrous capsule structure. The study identifies the core regulatory nodes at each stage. Additionally, it explores potential therapeutic strategies for tophi and outlines future research directions. Together, these insights provide new therapeutic targets and a more comprehensive conceptual framework for early intervention and drug development. This research carries significant clinical and scientific value, with strong potential to improve outcomes for patients with chronic gout and to reduce the associated healthcare burden.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1847953","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T04:30:18Z","timestamp":1781065818000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["From uric acid to tophi: multistage molecular and cellular mechanisms of tophi formation"],"prefix":"10.3389","volume":"17","author":[{"given":"Heguo","family":"Yan","sequence":"first","affiliation":[{"name":"Yunnan University of Chinese Medicine","place":["Kunming, Yunnan, China"]},{"name":"Zhaotong Hospital of Traditional Chinese Medicine","place":["Zhaotong, Yunnan, China"]},{"name":"Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and 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