The role of redox-active iron, copper, manganese, and redox-inactive zinc in toxicity, oxidative stress, and human diseases.

Given the key importance played by the redox-active metals iron (Fe), copper (Cu), and manganese (Mn) in vital cellular processes, such as DNA synthesis, oxidative phosphorylation, the detoxification of reactive oxygen species (ROS), and angiogenesis, it is not surprising that their dysregulation plays a causative role in many human diseases. The same applies to redox-inactive zinc (Zn), which is involved in numerous biological functions, and serves as a structural element, a catalyst, and a participant in both intracellular and intercellular signaling and in maintaining immune system function. An imbalance in redox active (Fe, Cu, Mn) or redox inactive (Zn) metal ions, whether in excess or deficiency, is harmful and may disrupt the structural, regulatory, and catalytic roles of various antioxidant enzymes (superoxide dismutases (SODs), catalase (CAT), glutathione peroxidases (GPxs)), proteins, receptors, transporters, alter sulfhydryl homeostasis, generate high levels of ROS (e.g., hydroxyl radicals by the Fenton reaction), initiate lipid peroxidation, cause DNA damage, and lead to cell death via mechanisms such as ferroptosis, cuproptosis, cellular senescence, or inflammation. Maintaining redox homeostasis is essential for regulating numerous cellular signaling pathways. Redox-sensitive signaling pathways, such as the nuclear factor kappa B (NF-κB), mitogen-activated protein kinase kinase (MAPK), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways, form an intricate network that governs cellular responses to redox metal-induced oxidative stress and inflammation. The Nrf2 pathway is primarily responsible for mediating antioxidant defenses, whereas the NF-κB and MAPK pathways play roles in proinflammatory and stress-related responses. Dysregulation of redox-active Fe, Cu, Mn, and redox-inactive Zn can alter epigenetic regulatory mechanisms such as DNA methylation, histone modification, and non-coding RNA expression. The dyshomeostasis of metal ions is closely related to the pathogenesis of lung, renal, and gastrointestinal diseases, neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, and Huntington's disease), psychiatric conditions (schizophrenia), and various cancers. This review summarizes recent findings on the role of iron, copper, manganese, and zinc in maintaining physiological functions, redox homeostasis, and human diseases. See also the graphical abstract(Fig. 1).