Ferreting Out Ferroptosis: Extending the Mechanism of Action of RSL3 to the Selenoproteome in Colorectal Cancer

Although colorectal cancer is the second leading cause of cancer-related mortality in the United States, there has been limited progress in recent years in identifying new therapeutic options. However, cancer cells have been shown to be sensitive to ferroptosis, an iron-dependent lipid peroxide–induced form of cell death. In this issue of Cancer Research, DeAngelo and colleagues aimed to better understand the mechanisms underlying ferroptosis in colorectal cancer. However, using the ferroptosis-inducing small molecule RAS-selective lethal 3 (RSL3), they observed effects on colorectal cancer cells independent of RSL3’s presumed target, glutathione peroxidase 4. Investigating further, they found that RSL3 inhibits multiple antioxidant proteins in the peroxidase and selenoprotein families to more broadly affect reactive oxygen species and lipid peroxidation than previously assumed. Loss of ALKBH8, a tRNA methyltransferase responsible for modifying the selenocysteine-specific tRNA, broadly decreased selenoprotein activity and induced ferroptosis in colorectal cancer. This work identifies the selenoproteome as a therapeutic target in colorectal cancer via induction of reactive oxygen species, lipid peroxidation, and ferroptosis and adds to a growing body of literature on the potential utility of pro-oxidant mechanisms in cancer therapy. See related article by DeAngelo et al., p. 2788