2. Academic Validation
  3. Discovery of a potential anti-ischemic stroke agent by suppressing ferroptosis through the ATF3/SLC7A11/GPX4 pathway

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

  • Eur J Med Chem. 2025 Oct 15:296:117873. doi: 10.1016/j.ejmech.2025.117873.
Xiangyi Kong 1,  Penghui Wei 2,  Liying Meng 3,  Zongjiang Yu 4,  Xuemeng Liu 3,  Mei Li 3,  Yanan Zou 5,  Jianjun Li 6,  Guanzhao Wu 7
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China; Laboratory of Anesthesia and Brain Function, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China.
  • 2 Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China; Laboratory of Anesthesia and Brain Function, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China; Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, China.
  • 3 Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Shandong University, Qingdao, Shandong, 266035, China; Department of Central Laboratory, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, 266035, China.
  • 4 CAS Key Laboratory of Bio-based Materials, Qingdao Institute of BioEnergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, 266101, China.
  • 5 Qingdao Mental Health Center, 229 Nanjing Road, Qingdao, 266034, China.
  • 6 Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China; Laboratory of Anesthesia and Brain Function, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China. Electronic address: ljj9573@163.com.
  • 7 Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Shandong University, Qingdao, Shandong, 266035, China; Department of Central Laboratory, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, 266035, China. Electronic address: guanzhao.wu@email.sdu.edu.cn.
PMID: 40544652 DOI: 10.1016/j.ejmech.2025.117873
Abstract

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.

Keywords

ATF3; Cerebral ischemic stroke; Ferroptosis; Idebenone analog; Neuroprotection.

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