Each year in the US, severe TBI in children results in ∼7400 deaths and 60 000 hospitalizations. Fifty percent of surviving children with severe TBI have poor neurological outcome at six months. Severe TBI in children is thus a critical problem in desperate need of impactful therapies. Free radicals and oxidative stress have been uniformly accepted as universal pathogenic mechanisms of TBI prompting therapeutic use of antioxidants. Invariably, clinical trials of non-specific free radical scavengers/antioxidants failed. This suggests that true sources and mechanisms of TBI redox disbalance remain undefined, and represent a potential therapeutic opportunity. During the previous funding period we showed that lipid peroxidation after TBI in immature brain occurs as a result of controlled enzymatic reactions. We discovered that peroxidation of mitochondrial phospholipid cardiolipin (CL) represents a required stage of neuronal apoptosis after TBI in postnatal day (PND) 17 rats. We identified cytochrome c as a catalyst of CL peroxidation and showed that a mitochondria- targeted inhibitor of CL peroxidation suppressed TBI-induced apoptosis and preserved cognitive function in PND17 rats. Our latest work identified highly selective oxidation of arachidonic acid (AA) containing phosphatidylethanolamines (PE) by 15 lipoxygenase (15LOX) to be causative to ferroptosis. We discovered that PE binding protein 1 (PEBP1) complexes with 15LOX and changes its substrate specificity from free AA to AA esterified into PE to generate hydroperoxy-AA-PE death signals. Normally hydroperoxy-AA-PE are eliminated by combined action of glutathione peroxidase 4 (GPX4)/glutathione (GSH). Immature brain has lower GSH levels and GPX activity vs adult brain thus could be more vulnerable to ferroptosis upon injury. Indeed our preliminary data show that TBI leads to marked increase in expression and activity of 15LOX, and accumulation of oxidized AA-PE in PND17 rat brain. Furthermore, preliminary data in