N6022 Protects Against Ischemic Stroke by Attenuating Ferroptosis: A Novel Therapeutic Target

However, the protective role of N6022 in ischemic stroke and the specific mechanism by which it exerts its effects are not yet fully understood. Therefore, the aim of this study was to investigate whether N6022 could alleviate cerebral ischemia/reperfusion (I/R) injury by attenuating ferroptosis and to explore the underlying mechanisms. The ultimate goal is to uncover potential molecular medicine for the clinical treatment of ischemic stroke.

To simulate the human cerebral I/R process, we established both an MCAO/R mouse model and an OGD/R cell model. In both in vitro and in vivo experiments, we examined the impact of N6022 on MCAO/R-induced brain injury, neurological deficits, apoptosis, and ferroptosis in mice, as well as OGD/R-induced BV2 cell injury, apoptosis, and ferroptosis.

Our findings demonstrated that N6022 effectively protected against MCAO/R-induced brain damage and mitigated neurological deficits in mice, as well as alleviated OGD/R-induced BV2 cell damage. Mechanistically, N6022 increased the expression of GPX4 and SLC7A11 by promoting Nrf2 nuclear translocation. This, in turn, enhanced intracellular antioxidant capacity and attenuated ferroptosis. Notably, the positive effects of N6022 were partially reversed by the Nrf2-specific inhibitor ML385.

Furthermore, N6022 disrupted the interaction between GSNOR and GSTP1 by inhibiting GSNOR activity. This disruption subsequently increased the antioxidant capacity of GSTP1 and attenuated ferroptosis. Importantly, the specific knockdown of GSTP1 blocked the protective effects of N6022.

Overall, our study provides insights into the potential therapeutic effects of N6022 in ischemic stroke by targeting ferroptosis. We have unraveled specific mechanisms involving the Nrf2 pathway and GSNOR-GSTP1 interaction. These findings contribute to the development of potential molecular medicine for the clinical treatment of ischemic stroke.