Fig. 2: Doxorubicin-induced ferroptosis.
From: Regulated cell death pathways in doxorubicin-induced cardiotoxicity
Schematic representation of doxorubicin-induced ferroptosis pathway. Doxorubicin treatment results in iron overload through upregulation of TfR and inactivation of ferritin. Free iron complexes with doxorubicin and through the Fenton reaction create reactive oxygen species (ROS). Doxorubicin induces lipid peroxidation by inhibiting cytosolic and mitochondrial GPX4 resulting in ferroptosis. In the mitochondria, doxorubicin causes iron overload by blocking MitoFer and ABCB8. In the nucleus, activation of NRF2 results in upregulation of HMOX1 leading to heme degradation and resulting in excess free iron and ferroptosis. Tf transferrin, TfR transferrin receptor, IRP iron response regulatory protein, IRE Iron response element, NRF2 nuclear factor erythroid 2-related factor, HMOX1 heme oxygenase 1, PUFA polyunsaturated fatty acids, Lipid-OO lipid peroxides, GSH reduced glutathione, GPX4 glutathione peroxidase, GSSG glutathione disulfide, H2O2 oxygen peroxide, MitoFer mitochondria ferritin. ABCB8 ATP-binding cassette sub-family B member 8, ROS reactive oxygen species.
