Astrocytic FTO-dependent m6A demethylation drives sevoflurane-induced perioperative neurocognitive disorders in mice

The pathogenesis of perioperative neurocognitive disorders (PND) involves a complex interplay of genetic vulnerability and environmental insults, with epigenetic regulation acting as a dynamic mediator. However, the cell-specific epitranscriptomic responses to perioperative stressors like sevoflurane anesthesia, and their functional consequences for cognitive decline, are not well defined. Here, we report that the m6A demethylase FTO is significantly upregulated in the medial prefrontal cortex (mPFC) of male mice exposed to sevoflurane anesthesia. Astrocytic FTO, but not neuronal or endothelial FTO, is highly sensitive to sevoflurane exposure. Conditional knockout of FTO in astrocytes attenuated sevoflurane-induced cognitive deficits, while astrocyte-specific FTO overexpression exacerbated sevoflurane-induced cognitive deficits. Mechanistically, astrocytic FTO mediated m6A demethylation of glutamate transporter-1 (GLT-1) mRNA, leading to enhanced GLT-1 protein expression and aberrant glutamatergic transmission. Sevoflurane exposure disrupted synaptic transmission, neuronal morphology, and calcium activity in the mPFC, which were rescued by astrocytic FTO deletion. Supplementation with the methyl donor S-adenosylmethionine (SAMe) normalized m6A levels and improved cognitive performance. This study demonstrates that astrocytic FTO is a critical epitranscriptomic modulator of sevoflurane-induced PND and a potential therapeutic target for PND. Significance Statement PND are a major clinical concern for which effective mechanism-based interventions are lacking. This study identifies astrocytic FTO as a cell-type-selective epitranscriptomic driver of sevoflurane-induced PND and establishes that its m6A-demethylase activity disrupts glutamate homeostasis by post-transcriptionally regulating the astrocytic glutamate transporter GLT-1. Astrocyte-restricted deletion of FTO preserves synaptic transmission, neuronal structure, and calcium dynamics, thereby preventing cognitive decline, while astrocytic FTO overexpression exacerbates deficits. Therapeutic restoration of m6A methylation with the methyl donor SAMe normalizes the epitranscriptomic landscape and rescues cognitive function. These findings reveal astrocytic m6A regulation as a previously unrecognized pathogenic mechanism and a druggable target for PND.