Ferrous Iron-Dependent Pharmacology

The recent emergence of oxidation state selective probes of cellular iron has produced a more nuanced understanding of how cells utilize this crucial nutrient to empower enzyme function, and also how labile ferrous iron contributes to iron-dependent cell death (ferroptosis) and other disease pathologies including cancer, bacterial infections, and neurodegeneration. These findings, viewed in light of the Fenton chemistry promoted by ferrous iron, suggest a new category of therapeutics exhibiting ferrous iron-dependent pharmacology. While still in its infancy, this nascent field draws inspiration from the remarkable activity and tremendous clinical impact of the antimalarial artemisinin. Here, we review recent insights into the role of labile ferrous iron in biology and disease, and describe new therapeutic approaches designed to exploit this divalent transition metal. Iron cycles between the ferric and ferrous oxidation states to empower enzyme function but also during its uptake, export, and storage, with the ferrous state being generated transiently and in limited concentrations to prevent oxidative damage to the cell.Until very recently, it has not been possible to study the ferrous ion specifically, largely due to its much poorer ligation by small molecule or protein siderophores, as compared to the ferric ion.The emerging role of ferrous iron in a form of iron-dependent cell death (ferroptosis), and in supporting the proliferation of some of the most aggressive cancers has given new urgency to the study of cellular ferrous iron in biology and disease.The clinical success of the antimalarial artemisinin provides inspiration as well as a chemical and conceptual framework for the development of a new class of therapeutic agents exhibiting ferrous iron dependent pharmacology.