- Anthonymuthu, Tamil S;
- Tyurina, Yulia Y;
- Sun, Wan-Yang;
- Mikulska-Ruminska, Karolina;
- Shrivastava, Indira H;
- Tyurin, Vladimir A;
- Cinemre, Fatma B;
- Dar, Haider H;
- VanDemark, Andrew P;
- Holman, Theodore R;
- Sadovsky, Yoel;
- Stockwell, Brent R;
- He, Rong-Rong;
- Bahar, Ivet;
- Bayır, Hülya;
- Kagan, Valerian E
Hydroperoxy-eicosatetraenoyl-phosphatidylethanolamine (HpETE-PE) is a ferroptotic cell death signal. HpETE-PE is produced by the 15-Lipoxygenase (15LOX)/Phosphatidylethanolamine Binding Protein-1 (PEBP1) complex or via an Fe-catalyzed non-enzymatic radical reaction. Ferrostatin-1 (Fer-1), a common ferroptosis inhibitor, is a lipophilic radical scavenger but a poor 15LOX inhibitor arguing against 15LOX having a role in ferroptosis. In the current work, we demonstrate that Fer-1 does not affect 15LOX alone, however, it effectively inhibits HpETE-PE production by the 15LOX/PEBP1 complex. Computational molecular modeling shows that Fer-1 binds to the 15LOX/PEBP1 complex at three sites and could disrupt the catalytically required allosteric motions of the 15LOX/PEBP1 complex. Using nine ferroptosis cell/tissue models, we show that HpETE-PE is produced by the 15LOX/PEBP1 complex and resolve the long-existing Fer-1 anti-ferroptotic paradox.