Iron Metabolism: From Inflammation to Cancer

Review Article

Ann Hematol Oncol. 2021; 8(6): 1351.

Iron Metabolism: From Inflammation to Cancer

Di Paola A¹, Tortora C², Argenziano M², Di Leva C² and Rossi F²*

1Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Via S Maria di Costantinopoli, Italy

2Department of Woman, Child and General and Specialist Surgery, University of Campania “Luigi Vanvitelli”, Via L De Crecchio, Italy

*Corresponding author: Rossi F, Prof., MD. Department of Woman, Child and General and Special Surgery, University of Campania “Luigi Vanvitelli” Via De Crecchio, 4 - 80138 Naple, Italy

Received: April 11, 2021; Accepted: May 13, 2021; Published: May 20, 2021


Iron is a trace element essential for several physiological cell functions and any alteration in its metabolism could be associated to the onset of several disorders. Cells normally avoid any dysregulation, activating fine molecular mechanisms to balance iron uptake, utilization, recycling, storage and export. The main “actors” in this event are hepcidin, ferroportin, ferritin and transferrin, both at cell and systemic level. Dysregulation in iron homeostasis is closely related to inflammation onset and perpetuation, osteoporosis and cancer progression. During inflammation, it has been observed a reduction in circulating iron as direct consequence of increase in ferritin levels, aimed to contain inflammatory processes and in many cases to restore the immune response. Iron overload directly promotes bone resorption and inhibits bone formation inducing osteoporosis. Moreover, iron cellular accumulation is responsible for ROS production with consequent DNA damage and neoplastic transformation of cells. In conclusion, even though many molecular mechanisms have to be clarified, targeting iron and also the mediators of its metabolism could be useful to manage a great variety of disorders, such inflammation, immune diseases, osteoporosis and cancer.

Keywords: Iron metabolism; Inflammation; Osteoporosis; Cancer; Ironrelated pathologies


Iron is a very important trace element for organic systems, in particular in literature its vital role is well documented especially in mammal cells [1,2]. Iron is physiologically involved in several biological processes such DNA synthesis and repair, cellular metabolism and signaling [3,4], synthesis of hemoglobin, neurotransmission, cell growth and differentiation, immunity and others [5,6]. Considering the importance of iron in cell biology, a deregulation in its metabolism could damage cells, tissues and organ functions. For this reason, sophisticated molecular mechanisms are necessary to coordinate and maintain a proper homeostasis among iron uptake, utilization, recycling, storage and export [5,7]. Iron levels are normally equal to 3-4 gr with a daily loss of 1-2 mg [8] and these standard range is guaranteed by several key proteins: hepcidin, Ferroportin (FPN-1), ferritin and Transferrin (TF) are the principal regulators [9]. Hepcidin is a peptide hormone produced by liver and responsible for degradation and inhibition of FPN-1 [10]. FPN- 1is the only known iron exporter located on enterocyte basolateral membrane, where it mediates the dietary iron absorption as ferrous ion [11]. FPN-1 also limits the iron recycling from hepatocytes and macrophages, that are the cells principally involved in intracellular iron storage as ferritin [12,13]. TF is instead responsible for binding serum iron and delivering it to target cells expressing Transferrin Receptor 1 (TFR-1) that is triggered for the internalization of iron/ transferrin/TFR-1 complex [14]. In human beings systemic iron levels are principally controlled by hepcidin- FPN-1 axis [15], even though genetics and structure-function evaluations are ongoing to better clarify the exact molecular mechanism underlying their interaction [16-18]. Hepcidin is certainly the key protein in regulating iron levels and it could also serve as inflammatory marker [19]. During infection or inflammation its expression increases as consequence of pro-inflammatory cytokines production, especially of IL-6. Hepcidin binds FPN-1 inhibiting both bowel iron absorption and iron mobilization from hepatocytes and macrophages [20]. Therefore, during inflammation and infection processes, a protective condition known as “hypoferremia” develops to limit the vicious circle below inflammatory processes (iron-mediated activation of pro-inflammatory macrophages and further production of proinflammatory mediators [3]) and also to counteract the pathogens which metabolism depends on iron utilization. Dysregulation in iron metabolism is observed also in neurodegeneration [21] and cancer [22]. Iron indeed mediates the production of reactive oxygen species (ROS) by the Fenton reaction, thus inducing DNA damage, protein and lipid modifications, tumor microenvironment alteration and other events involved in tumor onset and progression [23-25]. Also in non-pathological conditions, the evaluation of ferritin and hepcidin levels could be useful indicator of circulating iron concentration. For example, during pregnancy hepcidin increases in the first trimester, while in the second and third ones it decreases principally to facilitate the absorption of dietary iron [26]. Biological systems normally work to avoid or compensate both excess and deficiency of iron. The excess is principally genetic (hereditary hemochromatosis, HH), but it could be also related to poor erythropoiesis or to secondary iron overloading conditions (i.e. transfusion-dependent thalassemia) [27,28]. Similarly, iron deficiency could cause health problems, among them the most common is iron deficiency anemia [5, 29, 30], but also cognitive complications in children [31-33]. Iron deficiency anemia is a group of sideropenic anemias characterized by low level of iron in plasma, low iron store, low transferrin saturation and other marks [32]. In the last decade, several authors described the involvement of iron and all the molecules responsible for its metabolism in pathogenesis of many other disorders, also extremely spread and burdensome for public health. In particular, this review has the aim to describe the involvement of iron metabolism in the pathogenesis of inflammation, osteoporosis and cancer, which represent the most common and diffuse health burden in humans (Figure 1).

Citation: Di Paola A, Tortora C, Argenziano M, Di Leva C and Rossi F. Iron Metabolism: From Inflammation to Cancer. Ann Hematol Oncol. 2021; 8(6): 1351.