Figure 3.

Examples of inducing ferroptosis to overcome cancer therapy resistance. A: activated expression of the transcription factor ZEB1 can induce epithelial cancer cells to undergo EMT and convert to a more mesenchymal, therapy-resistant state. Also, after many rounds of chemotherapy, the surviving cells can acquire mesenchymal characteristics. These mesenchymal cancer cells exhibit downregulation of NRF2 target genes, lower levels of NADPH and GSH, and higher dependence on GPX4, which are prone to ferroptosis induced by inactivation of GPX4. B: in normal hepatocytes, LIFR facilitates SHP1’s ability to inhibit the K63-linked polyubiquitination and activity of TRAF6, thereby inactivating NF-κB. In liver cancer cells, loss of LIFR leads to activation of NF-κB signaling and overproduction of the NF-κB target LCN2, which is a secreted iron-sequestering cytokine. This lowers free Fe²⁺ levels in liver cancer cells and renders them resistant to ferroptosis-inducing drugs (e.g., sorafenib), which can be targeted by an LCN2-neutralizing antibody. EMT, epithelial-mesenchymal transition; Fe³⁺, ferric iron; Fe²⁺, ferrous iron; GPX4, glutathione peroxidase 4; GSH, glutathione; LCN2, lipocalin 2; LIFR, leukemia inhibitory factor receptor; TRAF6, tumor necrosis factor receptor-associated factor 6.