HRI is responsible for the adaptation of microcytic hypochromic anemia in iron deficiency. In iron deficiency, heme concentration declines, which leads to HRI activation and inhibition of globin synthesis as illustrated in Figure 1. This results in decreased hemoglobin and total protein content in Hri^+/+ RBCs. In the absence of HRI (Hri^−/−), protein synthesis continues in the face of heme deficiency, resulting in excess globins. These heme-free globins are unstable and precipitate as inclusions (marked in green) in RBCs and their precursors, causing destruction of these cells. Hri^−/− RBCs are of normal cell size and slightly hyperchromic. However, Hri^−/− mice have decreased RBC number, reticulocytosis, and splenomegaly.