Ferroptosis‐Driven Neuronal Damage Exacerbation in Diabetic Stroke: Implications of SLC7A11 Inhibition

作者：Siyuan Liu, Min Liu, Binbin Wang, Miao Sun, H. J. Yang, Mengyao Qu, Libin Ma, Likai Shi, Yuxiang Song, Peng Li, Lulu Zhou, Wugang Hou, Weidong Mi, Yulong Ma · 发表于：CNS Neuroscience & Therapeutics · 年份：2026 · DOI：10.1002/cns.70830 · 被引用次数：1 · 研究领域：Ferroptosis and cancer prognosis、Trace Elements in Health、Cholesterol and Lipid Metabolism

BACKGROUND: Diabetes mellitus is a known contributor to worsened neurological outcomes following ischemic stroke, yet the underlying mechanisms remain elusive. Emerging evidence links ferroptosis to the extent of neuronal damage postischemic stroke. However, the role of ferroptosis in the context of diabetic stroke remains uncharted. SLC7A11, a key player in cellular antioxidant defense and ferroptosis regulation, has unexplored functions in diabetic cerebral ischemia/reperfusion. METHODS: In this study, we employed leptin receptor deficient (db/db) mice and wild-type (WT) littermates to model cerebral ischemic stroke. We harnessed quantitative proteomics to identify differentially expressed proteins and uncover potential signaling pathways. Infarct volume was assessed via 2,3,5-triphenyltetrazolium chloride staining. Neurobehavioral tests, immunohistochemistry, and immunofluorescence staining were employed to evaluate neuronal injury. The expression of SLC7A11 was assessed using Western blot and immunofluorescence staining. Dihydroethidium staining, flow cytometry, immunofluorescence staining, transmission electron microscopy, immunohistochemistry, and ELISA were used to assess ferroptosis. Furthermore, an adeno-associated viral 9 (AAV9) vector encoding SLC7A11 was utilized to validate the protective potential of neuronal SLC7A11 overexpression during diabetic stroke. RESULTS: Diabetic stroke mice exhibited exacerbated cerebral injury, with differentially expressed proteins ...