ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2025
D2HGDH Deficiency Regulates Seizures through GSH/Prdx6/ROS-Mediated Excitatory Synaptic Activity.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- DIRAS2 modulates MAPK pathway-mediated ferroptosis to regulate excitation/inhibition balance and seizure susceptibility.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- JC124 confers multimodal neuroprotection in epilepsy by suppressing NLRP3 inflammasome activation: evidence from animal and human neuronal models.Cell communication and signaling : CCS · 2025Article
- D2HGDH Deficiency Regulates Seizures through GSH/Prdx6/ROS-Mediated Excitatory Synaptic Activity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Neutrophils: a Central Point of Interaction Between Immune Cells and Nonimmune Cells in Rheumatoid Arthritis.Clinical reviews in allergy & immunology · 2025Review
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Authors and funding
15 authors.
Funding
Abstract
Current antiepileptic drugs are ineffective in one-third of patients with epilepsy; however, identification of genes involved in epilepsy can enable a precision medicine approach. Here, it is demonstrated that downregulating D-2-hydroxyglutarate dehydrogenase (D2HGDH) enhances susceptibility to epilepsy. Furthermore, its potential involvement in the seizure network through synaptic function modulation is investigated. D2HGDH knockdown reduces the glutathione reduced (GSH)/glutathione oxidized (GSSG) ratio and elevates reactive oxygen species (ROS) levels within neurons. Oxidative stress may play a crucial role in the pathogenesis of epilepsy. The specific contribution of each pathway varies among patients, highlighting the complexity of this disease. In this study, downregulation of D2HGDH affects modulation of ROS levels, synaptic transmission, and seizure susceptibility. Furthermore, the acid calcium-independent phospholipase A2 (aiPLA2) inhibitor, MJ33, restores the GSH/GSSG balance and reverses the increase in ROS levels caused by D2HGDH knockdown, resulting in remission of epilepsy-related behaviors. The results demonstrate that downregulation of D2HGDH affects synaptic function by regulating ROS production. These findings support the use of targeted gene therapy as a potential alternative to antioxidant-based treatments for refractory epilepsy.
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