Figure 3.

Possible mechanisms of inducing ferroptosis. Ferroptosis is a caspase independent cell death characterized by generation of lipid peroxides. Usually, under normal homeostasis if a cell needs to undergo ferroptosis, the cell enhances the generation of lipid peroxides with the help of various genes. Briefly, under unfavourable conditions, cellular ROS would be elevated which signals the cell membrane to incorporate fatty acids via LPCAT-3 enzyme, the fatty acids incorporated cell membrane would be further esterified by the ASCL-4 leaving poly unsaturated fatty acids (PUFAs) and acyl CoA. PUFAs would then interact with the hydroxyl free radicals produced by the generated ROS via LOX enzyme which requires ferrous iron through a process called Fenton reaction. Interestingly, there are two ways to induce ferroptosis in CSCs. The first mechanism to induce ferroptosis is by inhibiting SLC7A11. SLC7A11 is a cys-glu antiporter that imports cystine inside the cell by simultaneously exporting glutamate in a 1:1 ratio. The imported cystine is then reduced to two molecules of cysteine, which is then coupled with glutamate and glycine to form GSH. The formed GSH now acts as a co-factor for GPX4 and catalyses the conversion of lipid peroxides into lipid hydroxides, thereby halting ferroptosis. Secondly, ferroptosis could also be induced by iron chelators which degraded ferritin thereby enhancing LOX activity.