Therapeutic potential of zinc supplementation in rheumatoid arthritis: clinical evidence, molecular mechanisms, and formulation-specific effects.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder primarily affecting the synovial joints, characterized by persistent synovitis, progressive joint destruction, and systemic complications that contribute to significant morbidity. Despite advances in disease-modifying anti-rheumatic drugs and biologic therapies, many patients fail to achieve sustained disease control or experience treatment-related adverse effects, highlighting the need for safe adjunctive strategies. Zinc, an essential trace element with critical roles in immune regulation, antioxidant defense, and inflammatory signaling, has gained increasing attention in the pathogenesis and management of RA. Clinical studies consistently report altered zinc homeostasis and reduced circulating zinc levels in RA, which are associated with increased disease activity, oxidative stress, and immune dysregulation. However, human interventional studies evaluating zinc supplementation remain limited, involve relatively small sample sizes, and report heterogeneous findings. In contrast, experimental studies in validated animal models have more consistently demonstrated anti-inflammatory and immunomodulatory effects of zinc, including modulation of macrophage and T-cell activation, cytokine production, synovial fibroblast behaviour, and bone remodelling. Importantly, the therapeutic effects of zinc appear to be formulation-dependent, as organic zinc salts, chelated forms, and emerging nano-based formulations have demonstrated superior bioavailability and anti-inflammatory efficacy compared with conventional inorganic salts. This review aims to explain the molecular and immunological mechanisms underlying the effect of zinc in RA, evaluates findings from clinical and preclinical studies of zinc supplementation, and highlights formulation-specific considerations relevant to clinical practice. While existing evidence supports the potential of zinc as a safe and beneficial adjunct to conventional RA therapy, further well-designed randomized clinical trials are required to establish optimal dosing strategies and identify patient populations most likely to benefit.