Authors
Yunfei Wang, Feng Ouyang, Run Feng, Zhe Ding, Jiafang Wang
Published in
Experimental brain research. Volume 244. Issue 7. Jun 15, 2026. Epub Jun 15, 2026.
Abstract
Postoperative cognitive dysfunction (POCD) is a prevalent neurological consequence in aged patients, with neuroinflammation and ferroptosis implicated in its pathogenesis. This study investigates whether dexmedetomidine (DEX) alleviates POCD by modulating the JPX/HIF-1α/DHODH axis.
Aged Sprague-Dawley rats received excision of the right common carotid artery to establish POCD. DEX (12 μg/kg) was administered preoperatively. Cognitive performance was evaluated through behavioral paradigms including spatial navigation tasks (Morris water maze) and recognition memory assessments (novel object test). Hippocampal ferroptosis markers (Fe2⁺, MDA, SOD, GSH) and protein levels (SLC7A11, GPX4, Iba1) were measured. BV-2 microglial cells were subjected to LPS treatment in vitro to induce neuroinflammation. RNA immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase assays were performed to validate JPX/HIF-1α/DHODH interactions. Rescue assays were used to verify the role of JPX/HIF-1α/DHODH axis on ferroptosis of BV-2 cells.
DEX ameliorated cognitive deficits and suppressed hippocampal ferroptosis. Mechanistically, JPX recruits HIF-1α to transcriptionally activate DHODH expression, while DEX upregulated JPX to facilitate HIF-1α-mediated DHODH transcription. In BV-2 cells, DEX attenuated LPS-induced ferroptosis, whereas JPX silencing abolished its effects. DHODH overexpression counteracted siJPX's exacerbation of ferroptosis.
DEX alleviates POCD by inhibiting microglial ferroptosis via the JPX/HIF-1α/DHODH axis, providing a novel therapeutic target for POCD intervention.
PMID:
42295409
Bibliographic data and abstract were imported from PubMed on 15 Jun 2026.
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