Ferroptosis, controlled by the selenoenzyme GPX4, is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids. iFSP1 is a potent, selective and glutathione-independent inhibitor of ferroptosis suppressor protein 1 (FSP1) with an EC50 of 103 nM. iFSP1 (0.001-1 μM; 24 h) dose-dependently inhibited the GPX4-knockout cell growth, but did not inhibit the wild type cell growth. Treatment with the ferroptosis inhibitor Lip-1 protects GPX4-knockout cells from iFSP1-induced ferroptosis. iFSP1 (3 μM; 24 h) resulted in an obvious toxicity of RSL3 (a ferroptosis inducer) in a panel of genetically engineered (FSP1-knockout) human cancer cell lines[3].
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