From multi-omics screening to functional validation: The SOD1-SIRT5 Axis as a potential mediator of ammonia-related neuronal injury and NAD⁺-based neuroprotection in epilepsy
- 1Department of Neurology, The Second People’s Hospital of Qinzhou, Qinzhou, 535000 Guangxi Zhuang Autonomous Region People’s Republic of China
- 2Department of Neurology, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Hedi Road No 85, Nanning, 530021 Guangxi Zhuang Autonomous Region China
- 3Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, No 85 Shuangyong Road, Nanning, 530021 Guangxi Zhuang Autonomous Region China
Abstract
While the excitation-inhibition imbalance theory has long dominated epilepsy research, the role of cerebral ammonia dysregulation remains underexplored. Herein, we integrated bioinformatics with multi-level experimental validation utilizing tissues from epilepsy patients, a kainic acid-induced chronic mouse model, and an in vitro magnesium-free neuronal model. Five core genes (SOD1, SIRT5, ALB, GFAP, and PLA2G2A) were identified to form a promising predictive model for epilepsy. Cerebral ammonia levels were significantly elevated across all models, accompanied by downregulation of SOD1, SIRT5, and NeuN, alongside significant hippocampal neuronal loss. Network pharmacology and molecular docking identified NAD⁺ as the top compound targeting both SOD1 and SIRT5. Functional studies revealed that overexpression of SOD1 or SIRT5, as well as NAD⁺ treatment, effectively reduced ammonia accumulation, increased neuronal viability, and restored NeuN expression. Notably, neither genetic overexpression nor NAD⁺ treatment directly altered baseline neuronal firing, indicating that their neuroprotective efficacy is mediated through mitigation of ammonia toxicity rather than direct suppression of hyperexcitability. Collectively, these findings suggest that cerebral ammonia dysregulation is associated with dysfunction of the SOD1-SIRT5 axis, which may contribute to AICD in epilepsy, and that restoring this axis via SOD1/SIRT5 overexpression or NAD⁺ reduces ammonia accumulation and promotes neuronal survival.
Graphical Abstract:
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s11011-026-02016-2.
Related
- miR-770 as a potential regulator of DNA methylation-related gene expression in glioblastoma: from in silico prediction to functional validation
- Zileuton Beyond Asthma: A Multifaceted 5-Lipoxygenase Inhibitor With Emerging Therapeutic Potential Across Inflammation, Cancer, Neuroprotection, and Fibrosis
- NRF2 signalling in environmental metal and metalloid neurotoxicity: distinguishing stress responses from functional neuroprotection
- GLP-1 receptor agonists as potential disease-modifying agents in Parkinson's and Alzheimer's disease: mechanisms, clinical trial evidence, and the neuroprotection horizon.
- Multi-omics and Functional Analyses Identify Cancer-associated Fibroblast-derived Insulin-like Growth Factor 1 as a Stromal Mediator of Lung Adenocarcinoma Progression.
BibTeX
@article{han2026from,
title = {{From multi-omics screening to functional validation: The SOD1-SIRT5 Axis as a potential mediator of ammonia-related neuronal injury and NAD⁺-based neuroprotection in epilepsy}},
author = {Jing Han and Ya Huang and Sijun Li and Caixia Xuan and Peiying Qin and Tingzhi Liu and Chunxiang Jiang and Xinhong Liang and Tingting Tan and Xing Wei and Chaoning Liu},
journal = {Metabolic Brain Disease},
year = {2026},
month = nov,
doi = {10.1007/s11011-026-02016-2},
url = {https://doi.org/10.1007/s11011-026-02016-2},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - From multi-omics screening to functional validation: The SOD1-SIRT5 Axis as a potential mediator of ammonia-related neuronal injury and NAD⁺-based neuroprotection in epilepsy
AU - Jing Han
AU - Ya Huang
AU - Sijun Li
AU - Caixia Xuan
AU - Peiying Qin
AU - Tingzhi Liu
AU - Chunxiang Jiang
AU - Xinhong Liang
AU - Tingting Tan
AU - Xing Wei
AU - Chaoning Liu
PY - 2026
DA - 2026/11/04
JO - Metabolic Brain Disease
DO - 10.1007/s11011-026-02016-2
UR - https://doi.org/10.1007/s11011-026-02016-2
AB - While the excitation-inhibition imbalance theory has long dominated epilepsy research, the role of cerebral ammonia dysregulation remains underexplored. Herein, we integrated bioinformatics with multi-level experimental validation utilizing tissues from epilepsy patients, a kainic acid-induced chronic mouse model, and an in vitro magnesium-free neuronal model. Five core genes (SOD1, SIRT5, ALB, GFAP, and PLA2G2A) were identified to form a promising predictive model for epilepsy. Cerebral ammonia levels were significantly elevated across all models, accompanied by downregulation of SOD1, SIRT5, and NeuN, alongside significant hippocampal neuronal loss. Network pharmacology and molecular docking identified NAD⁺ as the top compound targeting both SOD1 and SIRT5. Functional studies revealed that overexpression of SOD1 or SIRT5, as well as NAD⁺ treatment, effectively reduced ammonia accumulation, increased neuronal viability, and restored NeuN expression. Notably, neither genetic overexpression nor NAD⁺ treatment directly altered baseline neuronal firing, indicating that their neuroprotective efficacy is mediated through mitigation of ammonia toxicity rather than direct suppression of hyperexcitability. Collectively, these findings suggest that cerebral ammonia dysregulation is associated with dysfunction of the SOD1-SIRT5 axis, which may contribute to AICD in epilepsy, and that restoring this axis via SOD1/SIRT5 overexpression or NAD⁺ reduces ammonia accumulation and promotes neuronal survival. Graphical Abstract: Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s11011-026-02016-2.
SN - 0885-7490
SN - 1573-7365
ER -