Figure 6.

Molecular characteristics related to cancer cell‐selective lethality shared by small molecules indirectly inhibiting GPX4 and inducing HO‐1. Genetic or pharmacological inhibition of HO‐1 decreases the viability of cancer cells under basal conditions. When cancer cells are, however, exposed to electrophilic small molecules that activate NRF2 and evoke a strong expression of HO‐1, the accumulation of lipid hydroperoxides and a drop in cell survival are diminished by selective HO‐1 inhibition. Whether the often associated increase of HO‐1 and decrease of GPX4 are independent events or functionally linked is poorly understood. In nontransformed, normal cells, the NRF2/HO‐1 axis instead rather protects from lipid peroxidation and cell death. This antiferroptotic activity seems at least partially to be mediated by HO‐1. GPX4, glutathione peroxidase 4; HO‐1, heme oxygenase‐1; NRF2, nuclear factor erythroid 2‐related factor 2; ROS, reactive oxygen species. [Color figure can be viewed at wileyonlinelibrary.com]