Morin improves postoperative cognitive dysfunction by mediating the miR-138-5p/SIRT1 axis to regulate ferroptosis.

This study aimed to explore whether Morin could improve postoperative cognitive dysfunction (POCD) by inhibiting hippocampal ferroptosis through miR-138-5p/SIRT1. Morin improves the cognitive function of POCD mice by inhibiting the expression of miR-138-5p and promoting the expression of SIRT1 protein. When detecting ferroptosis-related indicators (such as GSH, MDA, and iron ion levels), it was found that miR-138-5p agomir blocked the regulatory effect of Morin on these indicators. Protein detection showed that Morin regulated the ferroptosis process by controlling the miR-138-5p/SIRT1 axis to affect the expression of p53, SLC7A11, and GPX4. In vitro cell experiments showed that after Erastin induction, the GSH level in HT22 cells decreased, the MDA and Fe(2+) contents increased, and the ROS fluorescence intensity increased; after Morin treatment, these oxidative stress indicators were significantly improved, the expression of SIRT1, SLC7A11 and GPX4 increased, and the expression of p53 decreased. The miR-138-5p mimic aggravated the upregulation of oxidative stress and the regulation of ferroptosis-related genes, while the miR-138-5p inhibitor had the opposite effect. Morin improved cognitive function and neuronal morphology in POCD mice by inhibiting miR-138-5p and upregulating SIRT1. It also inhibited ferroptosis through the miR-138-5p/SIRT1 pathway, further confirming its protective role in POCD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-025-34240-8.