Discovery of a potential anti-ischemic stroke agent by suppressing ferroptosis through the ATF3 -SLC7A11-GPX4 pathway

Ischemic stroke is a major cause of human health impairment worldwide, yet effective treatments are currently lacking. Idebenone plays a crucial role in stroke recovery therapy, but its efficacy in acute stroke treatment remains suboptimal. The development of novel IDE analogs is of great significance for the treatment of ischemic stroke.In this study, a series of novel IDE analogs were designed and synthesized. The oxygen-glucose deprivation-reoxygenation cell model and middle cerebral artery occlusion animal model were employed for in vitro and in vivo investigations, respectively. Neurological damage and prognosis were evaluated using techniques such as triphenyl tetrazolium chloride staining and behavioral scoring. Furthermore, non-targeted metabolomics and lentiviral transfection approaches were applied to elucidate the potential mechanisms underlying the neuroprotective effects of these compounds.Compound 1c was identified as the most promising candidate due to its potent neuroprotective effects. Our findings demonstrate that treatment with 1c reduces infarct size following ischemic injury and enhances neuronal survival. 1c alleviates neurodegeneration following ischemia-reperfusion injury by inhibiting ferroptosis. Furthermore, our findings reveal that the expression of activating transcription factor 3 is upregulated after I-R injury but is markedly suppressed upon treatment with 1c. Overexpression of ATF3 was shown to downregulate the expression of SLC7A11 and GPX4, critical regulators of ferroptosis, thereby facilitating ferroptosis following I-R injury.Our study demonstrates that treatment with 1c inhibits ferroptosis and mitigates ischemia-reperfusion injury partially through the ATF3-SLC7A11-GPX4 signaling pathway.