{
  "abstract": "Tuberous sclerosis complex (TSC), caused by pathogenic variants in TSC1 or TSC2 , is frequently associated with early-onset and drug-resistant epilepsy. Loss of hamartin–tuberin activity causes Rheb-dependent mTORC1 hyperactivation and provides the mechanistic basis for mTOR-directed treatment with everolimus, but mTORC1 activation alone does not fully account for variation in seizure burden or treatment response. Evidence from biochemical and disease-model studies indicates that TSC1/TSC2 also interacts with canonical Wnt/β-catenin signaling through GSK3β and Axin, while cellular metabolism may provide an additional point of convergence through AMPK-dependent regulation of TSC2. This narrative review examines the biochemical, neuronal, human-tissue, pharmacological, and clinical evidence for this Wnt–GSK3β–TSC2–mTOR framework and distinguishes established findings from context-limited, emerging, and hypothetical relationships. Everolimus remains the established mechanism-based therapy for TSC-associated refractory seizures, whereas metformin has the strongest TSC-specific clinical signal among the investigational metabolic approaches discussed. GLP-1 receptor agonists and direct GSK3β modulation remain preclinical or mechanistically speculative in this setting. Gene- and RNA-based approaches provide emerging precedents for pathway-selective intervention, but none has directly targeted the Wnt–GSK3β–TSC2 interface. The principal unresolved question is whether this signaling relationship operates in human TSC epileptogenic tissue. Direct tissue-level validation, followed by selective pathway interrogation and adequately powered therapeutic studies, is needed before Wnt-directed strategies can be considered clinically relevant in TSC-associated epilepsy.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 1,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Roaya S. Alqurashi"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dm226jpxsx7f0.bib",
  "cited_by": 0,
  "doi": "10.3389/fphar.2026.1972918",
  "fulltext_url": null,
  "id": "dm226jpxsx7f0",
  "issns": [
    "1663-9812"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1972918/full",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [],
  "openalex": null,
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-05",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/dm226jpxsx7f0.ris",
  "sources": [
    {
      "first_seen": "2026-11-05T12:21:25Z",
      "native_id": "10.3389/fphar.2026.1972918",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1972918/full"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "issn:1663-9812",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Wnt/β‐catenin–mTOR crosstalk in TSC-associated epilepsy: pharmacological evidence and therapeutic opportunities",
  "title_text": "Wnt/β‐catenin–mTOR crosstalk in TSC-associated epilepsy: pharmacological evidence and therapeutic opportunities",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T00:21:24Z",
  "url": "https://research.draconitic.com/paper/dm226jpxsx7f0",
  "venue": "Frontiers in Pharmacology",
  "versions": []
}