<scp>ERα</scp> Agonist Protects Aged Female Mice From Sevoflurane Neurotoxicity via <scp>PTEN</scp> Nuclear Translocation

ABSTRACT Background Repeated sevoflurane exposure has been associated with postoperative cognitive dysfunction, particularly in the aged population, yet the underlying mechanisms remain unclear. This study aimed to investigate whether PTEN nuclear translocation mediates sevoflurane‐induced hippocampal synaptic and cognitive deficits in aged female mice, and whether activation of ERα can mitigate these effects. Methods Aged female mice were exposed to repeated sevoflurane, followed by assessment of PTEN subcellular localization using Western blot and immunofluorescence. Synaptic integrity was evaluated by PSD95 and SYP expression and dendritic spine density in the hippocampal CA1 region. Cognitive performance was assessed with the Morris water maze and Y‐maze tests. PTEN nuclear translocation was inhibited using AAV‐PTEN‐K13R, while Erα activation was achieved using PPT, and its effects were further evaluated in the presence of AAV‐shAagab, a regulator of PTEN nuclear translocation. Results Repeated sevoflurane exposure significantly increased nuclear PTEN and decreased cytoplasmic PTEN, reduced PSD95 and synaptophysin expression, decreased dendritic spine density, and impaired spatial learning and working memory. Inhibition of PTEN nuclear translocation via AAV PTEN‐K13R restored synaptic protein levels, spine density, and cognitive performance. Erα activation with PPT suppressed PTEN nuclear translocation, preserved synaptic structure, and improved cognitive function, whereas AAV shAagab largely abolished these protective effects. Conclusion Our study demonstrates that PTEN nuclear translocation mediates sevoflurane‐induced synaptic and cognitive deficits in aged female mice, and that Erα activation mitigates these effects by modulating PTEN localization. These findings suggest that Erα‐mediated regulation of PTEN may represent a potential therapeutic pathway for mitigating anesthesia‐related cognitive dysfunction in the elderly.