Metallostasis remodeling in rheumatoid arthritis: focus on iron, copper, and zinc in the synovial microenvironment

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovitis, pannus formation, and progressive bone erosion. Although cytokine-targeted therapies have substantially improved clinical outcomes, a subset of patients still experience inadequate responses, ongoing structural damage, and a sustained disease burden. Metallostasis contributes to immunometabolic and redox regulation and influences cellular functional states; its disruption is better understood as a mismatch between systemic redistribution and local synovial enrichment or depletion, rather than as a simple increase or decrease in total elemental abundance. In RA, iron dyshomeostasis is reflected by the coexistence of systemic iron restriction and local joint iron enrichment; copper dyshomeostasis involves acute-phase redistribution and lysyl oxidase (LOX)-mediated matrix remodeling; and zinc dyshomeostasis is associated with a low-zinc phenotype, altered zinc transport, and modulation of immune signaling thresholds. Through effects on redox regulation, immune signaling, and extracellular matrix remodeling, disturbances in metal homeostasis may contribute to persistent inflammation, synovial invasion, and bone destruction. In this narrative review, we discuss the evidence base, mechanisms of action, and translational potential of iron, copper, and zinc in RA. Moving beyond whether metal levels are increased or decreased toward their distribution within the synovial microenvironment, associated changes in cellular function, and experimentally defined causal links may open new directions for stratification biomarker development and precision intervention in RA.