PCK2 Emerges as a Candidate Metabolic Node in Tuberous Sclerosis Complex: An Integrative Transcriptomic and Structural Study

Tuberous sclerosis complex (TSC) driven by TSC1/TSC2 mutations causes persistent mTORC1 activation and frequent epilepsy. How mTORC1 hyperactivity triggers neuronal hyperexcitability remains poorly understood. This work aimed to uncover hub genes and candidate therapeutics for TSC-related epilepsy. Multi-omics bioinformatic approaches, including gene set variation analysis, weighted gene co-expression network analysis, Random Forest and SHapley Additive exPlanations, were applied to TSC transcriptomic datasets. After cross-dataset validation, upstream transcription factors were predicted, and candidate drugs were assessed via molecular docking and molecular dynamics simulations. Endoplasmic Reticulum-stress pathways were enriched; PCK2 was recognized as a key hub gene with ATF4 as its upstream regulator. Carbamazepine was predicted to bind PCK2 at Gly254, Gly255 and Ser257, forming a relative stable complex with binding free energy of −37.61 kcal/mol. PCK2 may connect mTORC1 dysfunction, ER stress, mitochondrial metabolism and neuronal impairment in TSC epilepsy. Beyond sodium-channel actions, carbamazepine may target PCK2, which awaits experimental validation.