Identification and initial characterization of a potent inhibitor of ferroptosis

Ferroptosis is a form of iron-dependent cell death characterized by elevated lipid peroxides and reactive oxygen species (ROS). Glutathione (GSH) plays an essential role in scavenging ROS to maintain cell viability and acts as a cofactor of GSH peroxidase 4 (GPX4) that protects lipids from oxidation. We have previously described a novel class of small molecules that induce ferroptosis in certain types of cancer cells. These compounds induce ferroptosis by blocking the uptake of cystine required for GSH synthesis. Even though ferroptosis is a well-established form of cell death, signaling pathways that modulate this process are not known. Therefore, we used a panel of growth factors/kinase inhibitors to test effects on ferroptosis induced by our lead compound. We discovered that BMS536924, a dual inhibitor of insulin-like growth and insulin receptors, is a potent inhibitor of ferroptosis. Further investigation indicated that the anti-ferroptotic activity of BMS536924 does not lie in its ability to inhibit insulin signal transduction. Instead, we provide evidence that BMS536924 binds iron, an essential cofactor in ferroptosis. Our results suggest caution in interpreting the effects of BMS536924 in investigations of insulin signaling and uncover a novel ferroptosis inhibitor.

Automated summary

Ferroptosis is an iron-dependent form of cell death, and the BMS536924 compound is found to be a potent inhibitor of ferroptosis by binding iron rather than inhibiting insulin signaling. This discovery sheds light on a novel ferroptosis inhibitor and raises caution in interpreting the effects of BMS536924 on insulin signaling.