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Applying network approaches to whole tissue and single-nucleus transcriptomic data collected from mouse models of temporal lobe epilepsy and publicly available transcriptomic data from human temporal lobectomy samples, we confirmed a previously described pattern of rapid and transient induction of the Janus kinase\/signal transducer and activator of transcription (JAK\/STAT) pathway within days of epileptogenic insult. This was followed by a resurgent activation of the JAK\/STAT pathway weeks to months later with the onset of spontaneous seizures. Targeting the first wave of JAK\/STAT activation after epileptic insult did not prevent seizures. However, inhibition of the second wave with CP690550 (tofacitinib) over a 2-week period enduringly suppressed seizures, rescued deficits in spatial memory, and alleviated epilepsy-associated histopathological alterations. Seizure suppression lasted for at least 2 months after the final dose. These results indicate that reignition of inflammatory JAK\/STAT3 signaling in chronic epilepsy opens a window for disease modification with the US Food and Drug Administration\u2013approved, orally available drug CP690550.<\/jats:p>","DOI":"10.1126\/scitranslmed.adt0527","type":"journal-article","created":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T13:58:39Z","timestamp":1742392719000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":19,"title":["Disease modification upon 2 weeks of tofacitinib treatment in a mouse model of chronic epilepsy"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1203-5932","authenticated-orcid":true,"given":"Olivia R.","family":"Hoffman","sequence":"first","affiliation":[{"name":"Department of Neuroscience, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI 53705, USA."},{"name":"Molecular and Cellular Pharmacology Graduate 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