Metal ions-associated redox dyshomeostasis in fibrosis: Molecular mechanisms and therapeutics

Organ fibrosis is a common pathological feature of various chronic diseases with high morbidity and mortality, and represents a major threat to global public health. The pathogenesis of organ fibrosis involves multiple etiological factors and molecular mechanisms, posing enormous obstacles to the development of anti-fibrotic drugs. In recent years, the critical role of redox dyshomeostasis in fibrogenesis has been gradually clarified. Dysregulated metabolism of metal ions such as iron, copper, zinc, and calcium induces excessive reactive oxygen species (ROS) production, which triggers parenchymal cell injury, inflammatory responses, and fibroblast-to-myofibroblast transition (FMT), ultimately leading to excessive extracellular matrix (ECM) accumulation. Thus, targeting metal ions to restore redox homeostasis has become a novel anti-fibrotic strategy. This review systematically elucidates the mechanisms by which metal ion imbalances are involved in fibrosis through oxidative stress and further provides an overview and perspective on metal ion-targeted therapeutic strategies against fibrosis.