Disrupting the immune homeostasis: the emerging role of macrophage ferroptosis in autoimmune diseases

Abstract

Autoimmune diseases are a class of chronic disorders characterized by the aberrant activation of the immune system, where macrophages play a central role in regulating immune responses during disease onset and progression. Ferroptosis, a form of iron-dependent programmed cell death, has recently attracted significant interest due to its involvement in various pathological conditions. In macrophages, ferroptosis not only compromises cell viability but also disrupts immune homeostasis by promoting pro-inflammatory responses and suppressing anti-inflammatory pathways, thereby intensifying inflammation and exacerbating disease severity. While substantial progress has been made in elucidating macrophage ferroptosis in atherosclerosis and oncology, its precise mechanistic role in autoimmune diseases remains largely unexplored. This review systematically summarizes the molecular mechanisms of macrophage ferroptosis and its regulatory effects on immune homeostasis, with particular emphasis on its role in autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), multiple sclerosis (MS), and systemic sclerosis (SSc). Furthermore, we discuss potential therapeutic targets related to macrophage ferroptosis in these conditions. By integrating current knowledge, this review aims to provide a theoretical framework and novel perspectives for developing innovative therapeutic strategies targeting autoimmune diseases.