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Current treatment outcomes remain limited. Investigating the role of the epigenetic long non\u2010coding RNA NEAT1 in TSC\u2010related epilepsy and cognition is essential. RNA sequencing analysis of clinical tissue samples revealed that NEAT1 is differentially expressed in epileptogenic versus non\u2010epileptogenic tubers and enriched in the PI3K\u2010AKT signaling pathway. To prove and further investigate the functional role suggested by the earlier transcriptomic and pathway enrichment analyses, NEAT1\u2010overexpression and NEAT1\u2010knockdown TSC2 conditional knockout (CKO) mouse models, as well as TSC2\u2010KO cell models, are established. In vivo experiments demonstrated that NEAT1 knockdown reduced seizure frequency and improved spatial learning and working memory. Cellular analyses in TSC model further revealed that NEAT1 significantly regulates the PI3K\/AKT\/mTOR signaling pathway, neurotransmitter receptor balance, and outward potassium currents. Specifically, NEAT1 overexpression excessively activated the mTORC1 signaling, leading to changes in 4E\u2010BP1 and S6K and abnormal cell proliferation. Moreover, NEAT1 overexpression contributed to an imbalance in excitatory neurotransmitter receptors and outward potassium currents, resulting in neuronal hyperexcitability, whereas NEAT1 knockdown has the opposite effect. This study provides new insights into the transcriptional regulation of TSC\u2010related epilepsy, highlighting the therapeutic potential of NEAT1.<\/jats:p>","DOI":"10.1002\/advs.202504316","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T19:32:07Z","timestamp":1760556727000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["NEAT1 Promotes Epileptogenesis in Tuberous Sclerosis Complex"],"prefix":"10.1002","volume":"13","author":[{"given":"Suhui","family":"Kuang","sequence":"first","affiliation":[{"name":"Functional Neurosurgery Department National Children's Health Center of China Beijing Children's Hospital Capital Medical University Beijing 100045 China"},{"name":"Key Laboratory of Major Diseases In Children Ministry of Education Beijing 100045 China"},{"name":"Laboratory for Clinical Medicine Capital Medical University Beijing 100069 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