Youjin Shen , Wentao Liu , Zonghua Zhou , Jianwen He , Xiaokun Qi
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引用次数: 0
Abstract
Backgroud
Therapeutic strategies for cerebral ischemia/reperfusion (I/R) injury, an important contributor to neurological impairment and disability, exhibit limited efficacy. Reperfusion therapy intensifies neuronal damage by promoting iron deposition, ferroptosis (lipid peroxidation-associated iron-dependent cellular death), and reactive oxygen species (ROS) accumulation.
Methods
we investigated the role of the m6A demethylase FTO in modulating ferroptosis during cerebral I/R injury, using middle cerebral artery occlusion/reperfusion (MCAO/R) model rats and neuronal cells subjected to oxygen glucose deprivation/reoxygenation (OGD/R) as in vivo and in vitro experimental platforms, respectively. Neurological scores and cerebral infarction volumes were measured by TTC staining. FTO, OTUB1, and SLC7A11 levels, and FTO demethylase activity, were assessed by qRT-PCR, western blotting, and immunohistochemistry. MeRIP was applied to ascertain the m6A methylation status of OTUB1 mRNA. Apoptotic rates and cell viability were quantitatively aalyzed by flow cytometry and CCK-8 assay, respectively, while brain tissue apoptosis was evaluated using TUNEL staining.
Results
MCAO/R rat brains and OGD/R cells showed decreased FTO expression and increased OTUB1 m6A methylation. FTO overexpression upregulated OTUB1 by diminishing m6A methylation, consequently stabilizing SLC7A11 and reducing ferroptosis. FTO or OTUB1 silencing increased ferroptosis, while their co-overexpression enhanced neuroprotective effects. FTO overexpression reduced infarct volume and cell apoptosis, and improved neurological outcomes in vivo.
Conclusions
FTO enhanced OTUB1 expression via m6A demethylation, stabilizing SLC7A11, and inhibiting ferroptosis to alleviate cerebral I/R injury. The FTO/OTUB1/SLC7A11 pathway is a viable therapeutic target for ischemic stroke, providing novel perspectives on the molecular mechanisms underlying neuroprotection and proposing innovative m6A-based therapies.
期刊介绍：
The Journal of Stroke & Cerebrovascular Diseases publishes original papers on basic and clinical science related to the fields of stroke and cerebrovascular diseases. The Journal also features review articles, controversies, methods and technical notes, selected case reports and other original articles of special nature. Its editorial mission is to focus on prevention and repair of cerebrovascular disease. Clinical papers emphasize medical and surgical aspects of stroke, clinical trials and design, epidemiology, stroke care delivery systems and outcomes, imaging sciences and rehabilitation of stroke. The Journal will be of special interest to specialists involved in caring for patients with cerebrovascular disease, including neurologists, neurosurgeons and cardiologists.
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