Transition metal dyshomeostasis-associated macrophage dysfunction: potential roles in chronic metabolic diseases
4 affiliations
- 1The First Clinical Medical College, Shenyang Medical College
- 2Department of Forensic Medicine, Criminal Investigation Police University of China
- 3School of Public Health, Shenyang Medical College
- 4Liaoning Key Laboratory of Environmental Pollution and Microecology, Shenyang Medical College
Abstract
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.
Related
- PET Imaging of Tumor-Associated Macrophage Dynamics and Response to Clinical Treatment for Potential Translation
- Integrated Multiomic Analysis Reveals an EBV‐Associated MIF–SPP1+ Macrophage Axis Linking Tumor Stemness and Immune Dysfunction in Nasopharyngeal Carcinoma
- Damage-Associated Molecular Patterns and Trained Immunity of Monocyte-Macrophage Populations in Osteoarthritis: Potential Molecular Links and Therapeutic Opportunities.
- Polarized macrophage-derived microvesicles differentially modulate intestinal barrier dysfunction and endoplasmic reticulum stress in ulcerative colitis.
- A cell death screen identifies macrophage-depleting agents with therapeutic potential
BibTeX
@article{sun2026transition,
title = {{Transition metal dyshomeostasis-associated macrophage dysfunction: potential roles in chronic metabolic diseases}},
author = {Bixian Sun and Jinhan Yang and Yuanyuan Shen and Runyi Liu and Mingyue Ma and Yue Wang},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1950688},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1950688/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Transition metal dyshomeostasis-associated macrophage dysfunction: potential roles in chronic metabolic diseases
AU - Bixian Sun
AU - Jinhan Yang
AU - Yuanyuan Shen
AU - Runyi Liu
AU - Mingyue Ma
AU - Yue Wang
PY - 2026
DA - 2026/10/27
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1950688
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1950688/full
AB - 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.
SN - 1664-3224
ER -