Figure 4.

Ferroptosis in the Context of Iron-Overload in ICH. Glutathione is synthesized using cystine as a substrate for cysteine which is coupled to glutamate and glycine in two steps. Glutathione can be used as a reducing substrate for glutathione peroxidase (GPX4) to reduce polyunsaturated fatty acid (PUFA) lipid peroxides to PUFA-OHs and is oxidized to glutathione disulfide (GSSG). GSH can be recycled from GSSG by glutathione reductase at the expense of NADPH. In a high iron-overload situation such as ICH, iron is imported into the cell in a heme group (brown boxes) or otherwise via divalent metal transporter 1 (DMT1), transferrin receptor (TfR1), low-density lipoprotein receptor-related protein (LRP1), and proton-coupled folate transporter (HCP1). Heme degradation takes place via HO-1 or HO-2 (HO-1/2) which releases Fe(2+) into the cell that can participate in the Fenton reaction. Unregulated ferrous iron in the cell can react with hydrogen peroxide to form hydroxyl radicals which can generate PUFA radicals and eventually PUFA peroxides in the presence of oxygen which are quenched by GPx4. Iron overload may also activate HIF-PHDs and the expression of ATF4 death-associated genes.