Dexmedetomidine inhibits microglia ferroptosis to relieve postoperative cognitive dysfunction in elderly rats through JPX/HIF-1/DHODH pathway

Background: 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.

Method: 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.

Result: 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.

Conclusion: DEX alleviates POCD by inhibiting microglial Ferroptosis via the JPX/HIF-1α/DHODH axis, providing a novel therapeutic target for POCD intervention.