Ferroptosis is a recently identified
iron-dependent form of nonapoptotic cell death implicated in brain, kidney, and heart pathology. However, the biological roles of
iron and
iron metabolism in ferroptosis remain poorly understood. Here, we studied the functional role of
iron and
iron metabolism in the pathogenesis of ferroptosis. We found that
ferric citrate potently induces ferroptosis in murine primary hepatocytes and bone marrow-derived macrophages. Next, we screened for ferroptosis in mice fed a high-
iron diet and in mouse models of hereditary
hemochromatosis with
iron overload. We found that ferroptosis occurred in mice fed a high-
iron diet and in two knockout mouse lines that develop severe
iron overload (Hjv-/- and Smad4Alb/Alb mice) but not in a third line that develops only mild
iron overload (Hfe-/- mice). Moreover, we found that
iron overload-induced liver damage was rescued by the ferroptosis inhibitor
ferrostatin-1. To identify the genes involved in
iron-induced ferroptosis, we performed microarray analyses of
iron-treated bone marrow-derived macrophages. Interestingly, solute carrier family 7, member 11 (Slc7a11), a known ferroptosis-related gene, was significantly up-regulated in
iron-treated cells compared with untreated cells. However, genetically deleting Slc7a11 expression was not sufficient to induce ferroptosis in mice. Next, we studied
iron-treated hepatocytes and bone marrow-derived macrophages isolated from Slc7a11-/- mice fed a high-
iron diet.
CONCLUSION: We found that
iron treatment induced ferroptosis in Slc7a11-/- cells, indicating that deleting Slc7a11 facilitates the onset of ferroptosis specifically under high-
iron conditions; these results provide compelling evidence that
iron plays a key role in triggering Slc7a11-mediated ferroptosis and suggest that ferroptosis may be a promising target for treating
hemochromatosis-related tissue damage. (Hepatology 2017;66:449-465).