The Suppressing Role of Nitric Oxide in the Ferroptotic Cell Death Signal Transduction

Nitric oxide (NO⋅) is a small free radical and one of the most important messenger molecules in living organisms which is synthesized by nitric oxide synthase. Our recent studies revealed a critical role of NO⋅ in the regulation of ferroptosis, a newly identified type of redox-driven cell death program, which acts upon the catalytic activity of 15-lipoxygenase (15-LOX) complexed with PE-binding protein 1 (PEBP1). We performed lipidomics studies and all-atom molecular dynamics simulations which revealed the suppressing role of NO⋅ in generating a ferroptotic death signal, Hp-ETE-PE, by competing with O2 for access to the catalytic site and directly intereacting with an ETE-carbon-centered intermediate to yield nitrosylated PE species.