Targeting ferroptosis in breast cancer

摘要

Overview of ferroptosis pathways. Transferrin (Tf) with two ferric iron (Fe3+) combines with TFRC and then enters the cell through endocytosis. In endosomes, ferric iron is reduced to ferrous iron (Fe2+) and released into the cytoplasm through DMT1. Fe2+ is stored as ferritin or function in an active loose state termed “labile iron pool”. Ferritin can be degraded via ferritinophagy mediated by NCOA4 to release Fe2+ into the cytoplasm. It can also be encapsulated into a multivesicular body mediated by Prominin2 and then transported out of the cell in the form of an exosome. The P62/Keap1/NRF2/HO-1 pathway, inhibited by ARF, contributes to the increase in Fe2+ by catabolizing heme. HSPB1 is a negative regulator of ferroptosis by reducing iron uptake and inhibiting ROS production. After being acetized by acyl-CoA synthetase (mainly ACSL4), PUFA-CoA is integrated into the cell membrane as PUFA-LP by LPCAT3 and then oxidized through the Fenton reaction mediated by Fe2+ and enzymatic reaction mediated mainly by LOXs into lipid ROS, which is the main killer in ferroptosis. ETC of the mitochondrial contributes to the generation of lipid ROS, while GPX4 and ubiquinol transform lipid peroxidation into nontoxic production. FSP1 is responsible for the conversion of ubiquinone into ubiquinol by consuming NADPH. HMGCR mediates the production of MVA from HMG-CoA derived from acetyl-CoA. MVA provides ubiquinone for FSP1 via the mevalonate pathway and IPP for combination of Se to GPX4. GPX4 exerts its role in a GSH-dependent manner. GSH is synthesized from glutamate, cysteine, and glycine. Cysteine is derived from methionine via the sulfur transfer pathway and cystine. The transporter system xc−, composed by SLC3A2 and SLC7A11, is the cystine/glutamate antiporter that imports cystine into cells while exporting glutamate. The subunit SLC7A11 is upregulated by NRF2 and downregulated by p53 and BAP1. P53 also suppress ferroptosis by downregulating DDP4 and upregulating CDKN1A