Molecular underpinnings controlling ferroptotic cell death

Ferroptosis is a pharmacologically amenable form of regulated necrosis and marked by iron-dependent lipid peroxidation and metabolic constraints. Ferroptosis is involved in various disease contexts including cancer, ischemia/reperfusion injury and neurodegeneration. Due to its unique role in quenching phospholipid hydroperoxides, selenium-containing glutathione peroxidase 4 (GPX4) is considered as the key ferroptosis regulator. Genome-wide genetic screening efforts have recently identified ACSL4 as an additional and essential player in the ferroptotic death process. Despite the outstanding role for GPX4 in ferroptosis, little is known about the molecular details that regulate GPX4 function and stability. Therefore, a novel mouse line expressing a hypomorphic GPX4 allele was established. Using this model, we now show that a specific type of interneurons requires selenium in the active site of GPX4, which emerges to be the limiting factor for mammalian life. Moreover, selenium utilization by GPX4 appears to have evolved as prerequisite to prevent peroxide-induced GPX4 enzyme overoxidation, thereby protecting against ferroptosis. Current studies focus on how partially reduced forms of oxygen trigger the ferroptotic process in different disease contexts.