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

Ischemic stroke is a leading cause of morbidity and mortality worldwide. Despite its widespread impact, effective treatments remain limited. Idebenone (IDE) has shown promise in promoting recovery following stroke; however, its efficacy during the acute phase of ischemic stroke remains suboptimal. Therefore, the development of novel IDE analogs is of significant importance for improving outcomes in ischemic stroke treatment. Herein, we designed and synthesized a series of novel IDE analogs (1a–1g). An oxygen-glucose deprivation/reoxygenation (O/R) cell model and middle cerebral artery occlusion (MCAO) animal model were employed to investigate the effects of these drugs in vitro and in vivo, respectively. 1c was identified as the most promising candidate owing to its potent neuroprotective effects. Experimental analyses demonstrated that treatment with 1c reduced infarct size following ischemic injury and enhanced neuronal survival. 1c further alleviated neurodegeneration following ischemia/reperfusion (I/R) injury by inhibiting ferroptosis. Furthermore, our findings revealed that the expression of activating transcription factor 3 (ATF3) was upregulated after I/R injury, but markedly suppressed upon treatment with 1c. ATF3 overexpression downregulates the expression of SLC7A11 and GPX4, which are critical regulators of ferroptosis, thereby facilitating ferroptosis following I/R injury. Overall, our findings highlight the therapeutic potential of 1c in ischemic stroke and provide insight into the underlying mechanisms of its neuroprotective effects.