{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T07:24:09Z","timestamp":1763191449308,"version":"3.45.0"},"reference-count":75,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Renal ischemia\/reoxygenation triggers uremic encephalopathy (UE), culminating in cognitive and neural derangements. Despite its neuroprotective functions, the hippocampal repercussion of the estrogen receptor G protein\u2010coupled estrogen receptor 1 (GPER1) in UE remains uncharted, alongside the prospective involvement of RUNX2. In Silico virtual screening suggested that prunetin (PRU) may activate GPER1 and inhibit RUNX2. To validate these findings in vivo, male Sprague Dawley rats were allocated into five groups: placebo\u2010surgery (PS), PRU\u2010treated PS, untreated UE, PRU\u2010treated UE, and UE pretreated with G\u201015 (a selective GPER1 blocker) before PRU. Biochemically, PRU significantly restored hippocampal structure and behavioral functions impaired by UE, reduced serum IS levels, and replenished GPER1 expression. Additionally, it suppressed p\u2010AKT, p\u2010GSK3\u03b2, RUNX2, TLR4, and NF\u2010\u03baB, while enhancing cell survival by silencing the necroptotic signal (TICAM1\/RIPK1\/RIPK3\/MLKL) and restoring caspase\u20108. PRU also counteracted mitochondrial dysfunction by downregulating PGAM5 and p\u2010DRP\u20101. Crucially, these beneficial effects were nullified by G\u201015, confirming the role of activated GPER1 in mediating PRU's therapeutic effects. Collectively, PRU\u2010induced GPER1 orchestrated neural integrity signal UE\/AKT\/GSK\u20103\u03b2\/RUNX2, inflammatory axis UE\/TLR\u20104\/NF\u2010\u03baB, necroptosis pathway (TICAM1\/RIPK1\/RIPK3\/MLKL), preventing mitochondrial dysfunction by suppressing the PGAM5\/DRP\u20101 cue. These findings highlight the therapeutic potential of PRU in treating UE\u2010related hippocampal damage through GPER1 activation.<\/jats:p>","DOI":"10.1002\/ardp.70086","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T10:05:40Z","timestamp":1756893940000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["GPER1 Mediates Hippocampal Therapeutic Effect of Prunetin in Uremic Encephalopathy: Modulation of the RUNX2 Axis, TLR4 Cascade, Necroptosis, and Mitochondrial Dysfunction"],"prefix":"10.1002","volume":"358","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2707-9532","authenticated-orcid":false,"given":"Ahmed B.","family":"Hamed","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Biochemistry, Faculty of Pharmacy Future University in Egypt Cairo 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A.","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Veterinary Medicine Cairo University Giza Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8819-9891","authenticated-orcid":false,"given":"Hanan S.","family":"El\u2010Abhar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Cairo University Cairo 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