FOXM1 downregulation contributes to sevoflurane-induced microglial dysfunction via transcriptional downregulation of...

Postoperative cognitive dysfunction (POCD) is a common post-anesthesia complication that seriously impairs patient prognosis. Microglial M1/M2 polarization imbalance is a key link in POCD development. Forkhead box M1 (FOXM1) is downregulated in sevoflurane (SEV)-induced cell models, but whether it affects microglial M1/M2 polarization remains unreported. qRT-PCR and Western blot were employed to detect the mRNA and protein levels. Flow cytometry was used to evaluate the expression of M1 markers and M2 markers in microglia. ELISA was employed to detect inflammatory factors. Cellular oxidative stress status and mitochondrial membrane potential (MMP) were assessed using commercial kits. GO functional annotation and KEGG pathway enrichment analyses were performed on the top 500 protein-coding genes downstream of FOXM1. Bioinformatic prediction, ChIP assay, and dual-luciferase reporter assay were used to verify the regulatory relationship between FOXM1 and regulator of G protein signaling 10 (RGS10). SEV treatment significantly decreased FOXM1 expression in HMC3 cells (P < 0.001, P < 0.01). FOXM1 overexpression alleviated SEV-induced M1/M2 polarization imbalance, reduced inflammation (lowered inflammatory factors), and mitigated oxidative stress (with reduced ROS/MDA, increased SOD/GSH-Px, and ameliorated MMP depolarization). GO/KEGG analysis revealed FOXM1 downstream genes were enriched in pathways like MAPK and TNF signaling pathways. FOXM1 bound to the RGS10 promoter and enhanced its transcription. RGS10 silencing reversed the ameliorative effects of FOXM1 overexpression on SEV-induced cellular changes (M1/M2 polarization, inflammation, oxidative stress, and MMP). FOXM1 regulates RGS10 via direct binding to its promoter, thereby modulating microglial M1/M2 polarization, inflammation, and oxidative stress. This study identifies the FOXM1-RGS10 axis as crucial for SEV-induced microglial dysfunction, providing experimental evidence for POCD mechanism elucidation and potential target screening.