Wnt/β‐catenin–mTOR crosstalk in TSC-associated epilepsy: pharmacological evidence and therapeutic opportunities
Year: 2026
Type: article
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.
Source: Frontiers in Pharmacology
Author: Roaya S. Alqurashi
Institution: Umm al-Qura University
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7225336778