Metal Ion Metabolism: The Silent Catalyst of Pulmonary Fibrosis

Pulmonary fibrosis (PF) is a chronic, progressive, and destructive interstitial lung disease, mainly characterized by abnormal extracellular matrix deposition and an irreversible decline in lung function. Despite advances in understanding its pathogenesis, effective treatment remains limited. Emerging evidence highlights the crucial role of dysregulated metal ion metabolism in PF onset and progression. Essential trace elements such as iron, copper, calcium, and zinc are involved in redox homeostasis, mitochondrial function, signal transduction, and immune regulation under physiological conditions. However, under PF-related pathological stress, metal ion homeostasis is disrupted, leading to excessive reactive oxygen species generation, sustained inflammation, and cell death, all of which exacerbate fibrotic remodeling. Although numerous studies have investigated individual ion-related mechanisms, a comprehensive synthesis is lacking. This review systematically summarizes the current knowledge of iron, copper, calcium, and zinc dysregulation in PF and explores their roles in oxidative stress, immune imbalance, epithelial-mesenchymal transition, and fibroblast activation. Moreover, based on recent progress in regenerative medicine, we briefly discuss the potential of stem cell-based therapies in restoring metal ion homeostasis and mitigating fibrosis. This work aims to provide a theoretical basis for a deeper understanding of metabolic regulation in PF and for the development of novel therapeutic strategies.