Anesthesia inhalation agent sevoflurane induces perioperative cognitive impairment: Apelin/early growth response 1 axis induces ferritinophagy and exacerbates ferroptosis.

Sevoflurane is a widely used inhaled anesthetic for inducing and maintaining general anesthesia in surgical patients. After inhalation, sevoflurane crosses the alveolar capillary membrane barrier to enter the circulatory system and act on the central nervous system, producing anesthetic effects. Recent research has found that sevoflurane can induce ferroptosis and trigger neurological disorders. However, the exact process behind this is not yet understood. In this study, we used an integrated approach combining bioinformatics analysis with in vivo experiments to investigate the complex relationships between sevoflurane, ferroptosis, and ferritinophagy, along with their underlying mechanisms. By analyzing the sevoflurane anesthesia dataset (GSE139220) in the Gene Expression Omnibus database, we identified the Apelin/early growth response 1 axis as a potential ferroptosis-associated signaling pathway involved in sevoflurane-induced postoperative cognitive dysfunction. The results of in vivo experiment showed that sevoflurane could induce perioperative neurocognitive disorder by reducing the ferroptosis markers glutathione peroxidase 4, xCT, and early growth response 1, as well as increasing the ferritinophagy marker nuclear receptor coactivator 4. Importantly, Apelin-13, a subtype of apelin, reversed these effects. Therefore, we concluded that sevoflurane induces ferritinophagy by regulating the apelin/early growth response 1 axis, thereby exacerbating ferroptosis and inducing cognitive impairment. Apelin-13 may be a promising drug for inhibiting sevoflurane-induced perioperative neurocognitive disorder.