The crosstalk between iron metabolism and immune tolerance in autoimmunity

Iron metabolism has emerged as a critical regulator of immune homeostasis, influencing both innate and adaptive immune responses. Dysregulation of iron balance is increasingly recognized as a key driver of autoimmunity, contributing to oxidative stress, ferroptosis, immune cell dysfunction, and the breakdown of immune tolerance.

This review explores the complex interplay between iron metabolism and autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). We highlight how iron overload and deficiency impact immune cell differentiation, macrophage polarization, Treg/Th17 balance, and B cell activation, thereby promoting chronic inflammation and tissue damage. Moreover, we discuss disease-specific mechanisms such as iron accumulation in the CNS in MS, synovial iron overload in RA, and hepcidin-driven anemia and ferroptosis in SLE.

Emerging therapeutic approaches, including iron chelation, hepcidin modulation, ferroptosis inhibition, and microbiome-targeted interventions, are examined as potential strategies to restore immune tolerance and mitigate autoimmune pathology. Finally, we emphasize the need for precise iron-targeted therapies, integration with immunomodulatory treatments, and the development of reliable iron-related biomarkers to optimize clinical management of autoimmunity.