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<p>There is a vicious cycle between brain metabolism and epileptic seizures that compounds the deleterious consequences of seizures. Human epilepsy samples implicate cholesterol 25-hydroxylase (CH25H) in linking lipid metabolism and immunity. CH25H expression increased in microglia after status epilepticus, with its product 25-hydroxycholesterol (25-HC) accumulating in the hippocampus and blood. Thus, we generated microglia-specific <i>CH25H</i> knockdown mice to study the role of CH25H specifically in epilepsy. <i>CH25H</i> knockdown inhibited the assembly and activation of NLRP3 inflammasome and restrained the loss of neurons in the hippocampal area in epileptic mice. More importantly, <i>CH25H</i> knockdown reduced the number of recurrent seizures and time in seizure by electroencephalogram recording, which was partly reversed after 25-HC treatment. Untargeted metabolomics showed that another lipid metabolite, arachidonic acid, might be a potential biomarker of CH25H-mediated epilepsy. These findings suggest that microglial CH25H regulated the status epilepticus in a hydroxylase-dependent mechanism.</p>

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Microglial-Derived Cholesterol 25-Hydroxylase Promotes Epileptic Seizure and Neuroinflammation Mediated by NLRP3 Inflammasome and Lipid Metabolism

  • 期刊论文

  • 发表日期：

    2025年11月15日

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  • Haifeng Zhang,
  • Tiantian Su,
  • Xiaoke Wu,
  • Mengmeng Shi

摘要

There is a vicious cycle between brain metabolism and epileptic seizures that compounds the deleterious consequences of seizures. Human epilepsy samples implicate cholesterol 25-hydroxylase (CH25H) in linking lipid metabolism and immunity. CH25H expression increased in microglia after status epilepticus, with its product 25-hydroxycholesterol (25-HC) accumulating in the hippocampus and blood. Thus, we generated microglia-specific CH25H knockdown mice to study the role of CH25H specifically in epilepsy. CH25H knockdown inhibited the assembly and activation of NLRP3 inflammasome and restrained the loss of neurons in the hippocampal area in epileptic mice. More importantly, CH25H knockdown reduced the number of recurrent seizures and time in seizure by electroencephalogram recording, which was partly reversed after 25-HC treatment. Untargeted metabolomics showed that another lipid metabolite, arachidonic acid, might be a potential biomarker of CH25H-mediated epilepsy. These findings suggest that microglial CH25H regulated the status epilepticus in a hydroxylase-dependent mechanism.