ABSTRACT 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 notably enriched in ferroptosis. Ferroptosis inhibitors markedly ameliorated neuronal damage in diabetic stroke mice. Additionally, we uncovered inhibited SLC7A11 expression and heightened ferroptosis in the early stages of reperfusion during diabetic stroke. Neuron‐specific enforced expression of SLC7A11 mitigated neuronal lipid peroxidation and ferroptosis, providing neuroprotective effects against diabetic cerebral ischemic injury. These protective effects were underscored by the decreased infarct volume, enhanced neurological function, and increased neuronal survival. Conclusion Our study points to SLC7A11 inhibition‐mediated ferroptosis as a pivotal factor in the aggravated neuronal damage observed during diabetic stroke. This novel insight opens avenues for potential therapeutic targets in the management of diabetic stroke, focusing on interventions aimed at modulating ferroptosis or SLC7A11 expression.
Liu et al. (Sun,) studied this question.