This section will focus on the details of what is known about how doxorubicin treatment and type 2 diabetes mellitus (T2DM) causes dysregulation of cellular iron and increased oxidative stress. In-depth information on iron metabolism, doxorubicin, and T2DM and how these relate to iron regulation will be described. Regulation of iron storage will be proposed as an additional mechanism through which metformin may ameliorate oxidative stress induced by doxorubicin and T2DM. Iron MetabolismIron plays an essential role in virtually all organisms, from bacteria to humans. In addition to binding oxygen in heme, it participates in many other cellular events including DNA synthesis and electron transfer in the electron transport chain. Despite being the most abundant element on earth (97), iron has very low bioavailability. Iron is therefore highly conserved in organisms; Humans do not have an excretion pathway for iron, but instead regulate iron at the level of absorption. Once absorbed, iron continues to be regulated because it is also highly reactive with oxygen. Figure 1 shows the Haber-Weiss and Fenton reactions, which easily occur under physiological conditions with free iron and oxygen or hydrogen peroxide to produce free radicals. These free radicals will cause damage to the cell and contribute to oxidative stress (67, 97). Iron absorption, transport and storage are therefore highly regulated, and disruption of iron metabolism has been implicated in several diseases. The mechanism of iron absorption and transport is well known and is briefly described here. Nonheme iron and heme iron are absorbed into enterocytes via DMT1 and heme transporter protein 1, respectively ( 5 , 67 , 97 ). Once inside the enterocyte, iron can be stored in the... center of the paper... in the tissue, the iron-sulfur clusters dissociate, causing a conformational change and aconitase becomes IRP-1(3) . This has possible implications for the relationship between iron homeostasis, oxidative stress and metabolism which will be discussed in more detail later. In summary, iron is an important and highly reactive element involved in several cellular processes. Iron uptake occurs through DMT1 and heme transporter protein 1, is transported to cells via transferrin, and is endocytosed by binding to TfR1. Once inside the cell, iron is transferred to the mitochondria, stored in ferritin, or released into the labile iron pool. The transport of iron out of the cell occurs via ferroportin, of which hepcidin is a potent inhibitor. Iron homeostasis can be disrupted, which increases cellular oxidative stress and contributes to the etiology of several diseases (5, 30, 67, 97).