Targeting inducible nitric oxide synthase with 1400W mitigates septic acute lung injury through inhibiting SLC7A11/GPX4 mediated ferroptosis.

Accumulating evidence has indicated that lung ferroptosis is an important contributor to septic acute lung injury (SALI). Inducible nitric oxide synthase (iNOS) may be implicated in the regulation of bronchial epithelial ferroptosis. Nevertheless, the precise mechanisms by which iNOS modulates ferroptosis remain elusive. This study investigated whether iNOS selective inhibitor 1400w alleviates LPS-induced SALI and suppresses ferroptosis in mice. Additionally, RNA sequencing (RNA-seq), molecular docking, molecular dynamic simulation, Transmission electron microscope (TEM), and western blotting were employed to predict and evaluate the molecular mechanism of 1400w on LPS-induced ferroptosis in vivo. The results showed that the administration of 1400w markedly attenuated LPS-induced lung injury and facilitated pulmonary function in mice. Also, 1400w administration effectively suppressed bronchial epithelial ferroptosis induced by LPS in mice. Furthermore, molecular docking and molecular dynamics simulations revealed stable binding between GPX4 and iNOS, with 1400w modulating ferroptosis mediated by SLC7A11/GPX4 through targeting iNOS. Collectively, our research demonstrated that inhibition of iNOS might represent a potential therapeutic strategy to improve SALI by inhibiting ferroptosis.