Figure 1.

Cartoon diagram of iron homeostasis under normal (A) and iron overload conditions (B). Under normal conditions, the iron released from the iron nanoparticle drug complex binds transferrin proteins in the plasma and is endocytosed into the cell via the transferrin receptor protein (TrF1). Endocytosed iron is then shuttled to the cytoplasm via the divalent metal transporter 1 (DMT1) and is either stored by iron storage proteins such as ferritin, used in iron dependent molecules/processes, or exported out of the cell via ferroportin. Under iron overload conditions, transferrin becomes completely saturated by iron resulting in the down regulation of the TrF1 pathway. The remaining nontransferrin bound iron is then transported into the cell via nonspecific metal transporters, DMT and ZIP14. The excess intracellular labile iron can react with cellular oxygen forming toxic reactive oxygen species (ROS), which may result in oxidative damage to proteins, lipids, and DNA.