Iron and inflammation homeostasis are closely linked, yet previous studies on the association between serum iron levels and acute gout attacks have yielded inconsistent results. This study aims to investigate the role of iron in acute gout attacks and its underlying molecular mechanisms.

Serum samples were collected from patients with acute gout attacks, intercritical gout, and healthy controls to measure serum iron levels. In vivo, mouse models of iron deficiency, sufficiency, and overload were established by feeding iron-controlled diets for 8 weeks, and the effects on MSU crystal-induced peritonitis and arthritis were assessed. Bone marrow-derived macrophages (BMDMs) were pretreated with ammonium ferric citrate (FAC) followed by stimulation with LPS and MSU crystals. Inflammatory factor production and secretion, NLRP3 inflammasome activation, and NF-κB pathway activation were measured.

 Compared with healthy controls and the intercritical gout group, patients with acute gout attacks had significantly lower serum iron levels, which negatively correlated with C-reactive protein and erythrocyte sedimentation rate. Both in vitro and in vivo studies showed that iron reduced monosodium urate crystal-induced inflammation. Iron-overloaded mice exhibited reduced paw swelling, inflammatory cell infiltration, and NLRP3 inflammasome activation compared with normal iron-fed mice. Additionally, iron-overloaded mice showed decreased neutrophil infiltration and IL-1β secretion in peritoneal lavage fluid. In macrophages, iron suppressed NLRP3 and pro-IL-1β production via the NF-κB/MAPK pathway, thereby reducing NLRP3 inflammasome activation and inflammatory factor release.

Iron can significantly alleviate acute gout attacks through the NF-κB/MAPK pathway. Appropriate iron supplementation may be a potential treatment for acute gout.