Transition metal dyshomeostasis-associated macrophage dysfunction: potential roles in chronic metabolic diseases

Transition metals such as iron, zinc, and copper serve as indispensable cofactors in immunometabolic regulation. As central regulators of innate immunity, macrophages rely on strict metal homeostasis to maintain their functional plasticity. Studies have shown that transition metal dyshomeostasis is associated with aberrant macrophage polarization and sustained inflammatory responses. Such macrophage dysfunction may contribute to the initiation and progression of chronic systemic metabolic diseases. This review comprehensively summarizes the regulatory functions of essential transition metals in shaping macrophage inflammatory phenotypes and regulating metabolic reprogramming. We further clarify the molecular mechanisms by which metal-induced macrophage dysfunction participates in the pathogenesis of major metabolic diseases such as type 2 diabetes mellitus, metabolic dysfunction-associated steatotic liver disease, and atherosclerosis. We discuss how targeting intracellular metal homeostasis via selective metal chelators and novel metal-based nanomaterials represents a promising and innovative immunomodulatory therapeutic strategy. Essential transition metal homeostasis is a critical determinant of macrophage plasticity and appears to play a significant role in the pathogenesis of chronic metabolic diseases. Macrophage dysfunction induced by transition metal dyshomeostasis is associated with systemic insulin resistance and may contribute to tissue-specific damage within hepatic, vascular, and adipose microenvironments. Although the mechanistic foundations have been established, significant knowledge gaps remain regarding stage-specific variations and dose-dependent thresholds of metal-induced macrophage phenotypic shifts. Future research should prioritize the validation of metal-based biomarkers in clinical cohorts and the development of targeted ‘metal-homeostasis’ therapies to restore macrophage function, thereby providing a novel theoretical framework for the prevention and treatment of chronic metabolic disorders.