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Fig. 3 | Biomarker Research

Fig. 3

From: Targeting ferroptosis in breast cancer

Fig. 3

Published molecular mechanisms of ferroptosis in breast cancer. Based on the overview described in Fig. 1, some specific mechanisms are proposed in breast cancer. Low cell density triggers increased catabolism of neutral triglycerides from lipid droplets via ATGL to channel fatty acids to mitochondria for β-oxidation, producing ROS. A low cell density induces depletion of GSH via the RIPK1/RIPK3/MLKL/CHAC1 pathway. GSH is also inhibited by cystine deprivation via both a direct decrease in synthesis and the GCN2/eIF2α/ATF4/CHAC1 pathway. Activation of the RIPK1/RIPK3/MLKL pathway also induces mitochondrial fragmentation and ROS production, which could be suppressed by the mitochondrial ROS scavenger Necrox-5 and RIPK1 inhibitor Nec-1. Cellular ROS attack PUFA-PL to produce lipid ROS in the presence of LOXs and Fe2+, and the lipid ROS further induce ferroptosis. MTDH enhances the ability of cells to use intracellular glutamate to maintain respiratory chain activity. Cellular ROS can be reduced by NAC and trolox, and lipid ROS can be reduced by ubiquinol, GCH1/BH4, liproxstatin-1 and GPX4. GPX4 is inhibited by ECM detachment or a low density of cells, MTDH and inhibitors such as SAS, (1S, 3R) RSL3, ML162 and ML210. SAS also inhibits DMT1 and system xc-. The integrin α6β4 sustains GPX4 expression via Src and suppresses ACLS4 via Src and STAT3. Additionally, α6β4 attenuates the effect of erastin on xCT. The adhesion protein PVRL4 is necessary for α6β4 to exert its anti-ferroptotic function. The antiporter xCT is inhibited by erastin, SAS, sorafenib and MTDH. E2 upregulates expression of TFRC and secretion of transferrin, while ERα suppresses expression of TFRC. Administration of siramesine and lapatinib increases TFRC and decreases FPN1 expression, thus elevating the level of intracellular iron

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