N6022 Protects Against Cerebral Ischemia/Reperfusion Injury via Nrf2 and GSNOR/GSTP1 Pathways

While the role of N6022 in ischemic stroke remains unclear, this study investigated its potential to alleviate cerebral ischemia/reperfusion (I/R) injury by targeting ferroptosis. We established MCAO/R mouse and OGD/R cell models to simulate human cerebral I/R. Both in vitro and in vivo experiments revealed that N6022 effectively protected against MCAO/R-induced brain injury, neurological deficits, apoptosis, and ferroptosis in mice. Similar protective effects were observed in OGD/R-induced BV2 cells. Mechanistically, N6022 promoted Nrf2 nuclear translocation, leading to increased expression of GPX4 and SLC7A11, which enhanced intracellular antioxidant capacity and attenuated ferroptosis. This effect was partially reversed by the Nrf2 specific inhibitor ML385. Additionally, N6022 inhibited GSNOR, disrupting its interaction with GSTP1 and increasing GSTP1's antioxidant capacity, thereby attenuating ferroptosis. This effect was blocked by GSTP1 knockdown. Our findings highlight the therapeutic potential of N6022 for ischemic stroke treatment by targeting Nrf2 and GSNOR/GSTP1 pathways to inhibit ferroptosis.