Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron degenerative disease that leads to paralysis and eventual death. ALS is a particular concern for veterans, as military service is associated with increased risk of ALS. The root cause of ALS is the death of motor neurons; however, the modalities of motor neuron death in ALS remain unclear. Ferroptosis is an oxidative, iron-dependent cell death mechanism. Results from our prior research have shown that motor neurons are vulnerable to ferroptosis. Importantly, we showed recently that increased defense against ferroptosis resulted in significantly increased lifespan and ameliorated motor neuron degeneration in SOD1G93A mice, a widely used ALS mouse model, indicating that ferroptosis is a targetable vulnerability of motor neurons. However, at present, key questions about the roles of ferroptosis in motor neuron death of ALS remain unanswered. For example, it is unclear whether inhibition of ferroptosis at symptomatic stage can retard progression of motor neuron disease, and the contributions of ferroptotic stress of different cell types on pathogenesis of motor neuron disease remain unknown. To answer those questions, we have generated a novel mouse model with inducible expression of Gpx4, the master defender of ferroptosis, which allows us to inhibit ferroptosis genetically in both temporal and cell-type specific manners. In our preliminary study, we have also identified a small molecule compound with the ability to retard ferroptosis of motor neurons in vivo. To determine if ferroptosis-inhibiting compounds can retard motor neuron disease, we will test the efficacy of this compound in SOD1G93A mice. The overall hypothesis tested in this project is: inhibition of ferroptosis after disease onset will be effective in retarding progression of motor neuron disease and ferroptosis inhibition retards motor neuron disease in a cell-type specific manner. The results from this project will provide novel insights into the mechanisms of motor neuron degeneration of ALS, and importantly, could lead to new therapeutic strategies for ALS.