{
  "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.\n\nGraphical Abstract:\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s11011-026-02016-2.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Neurology, The Second People’s Hospital of Qinzhou, Qinzhou, 535000 Guangxi Zhuang Autonomous Region People’s Republic of China",
    "Department of Neurology, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Hedi Road No 85, Nanning, 530021 Guangxi Zhuang Autonomous Region China",
    "Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, No 85 Shuangyong Road, Nanning, 530021 Guangxi Zhuang Autonomous Region China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jing Han"
    },
    {
      "affs": [
        0
      ],
      "name": "Ya Huang"
    },
    {
      "affs": [
        1
      ],
      "name": "Sijun Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Caixia Xuan"
    },
    {
      "affs": [
        0
      ],
      "name": "Peiying Qin"
    },
    {
      "affs": [
        0
      ],
      "name": "Tingzhi Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Chunxiang Jiang"
    },
    {
      "affs": [
        0
      ],
      "name": "Xinhong Liang"
    },
    {
      "affs": [
        0
      ],
      "name": "Tingting Tan"
    },
    {
      "affs": [
        2
      ],
      "name": "Xing Wei"
    },
    {
      "affs": [
        0
      ],
      "name": "Chaoning Liu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9etayzdz7qkv1.bib",
  "cited_by": 0,
  "doi": "10.1007/s11011-026-02016-2",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13736451/",
  "id": "9etayzdz7qkv1",
  "issns": [
    "0885-7490",
    "1573-7365"
  ],
  "landing_url": "https://doi.org/10.1007/s11011-026-02016-2",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "2728|Epilepsy research and treatment"
    ]
  ],
  "openalex": "W7225249709",
  "pdf_url": null,
  "pmcid": "PMC13736451",
  "pmid": "42980871",
  "published": "2026-11-04",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/9etayzdz7qkv1.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T12:21:53Z",
      "native_id": "PMC13736451",
      "source": "pmc",
      "url": "https://doi.org/10.1007/s11011-026-02016-2"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2728|Epilepsy research and treatment",
      "subfield": "neurology"
    }
  ],
  "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",
  "title_text": "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",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:21:53Z",
  "url": "https://research.draconitic.com/paper/9etayzdz7qkv1",
  "venue": "Metabolic Brain Disease",
  "versions": []
}