Multi-omics analysis reveals sevoflurane exacerbates cognitive impairment in diabetic mice by disrupting lipid metabolism

Diabetes-associated cognitive dysfunction represents a global health challenge, yet the mechanisms by which anesthetics modulate cognitive function in diabetic states remain poorly understood. We systematically compared the effects of 2-hour brief exposure to sevoflurane (SEV) and propofol (PRO) on cognitive function and neuropathology in streptozotocin (STZ) -induced diabetic mice. Morris water maze and Y-maze tests revealed that SEV significantly exacerbated spatial memory and learning deficits in mice, while PRO showed no significant effects. Additionally, diabetic mice exhibited reduced NeuN⁺ neurons, increased β-amyloid deposition, and decreased SYN expression in the hippocampal CA1 region as examined by Immuno-fluorescence staining. Neither short-term SEV nor PRO exposure aggravated neuronal structural damage. Further transcriptomics revealed both anesthetics affected hippocampal neuron differentiation, but SEV uniquely perturbed fatty acid metabolism pathways. Metabolomics identified SEV-induced disruptions in lipid metabolism, marked by elevated hippocampal free fatty acids, phospholipids, as well as reduced lysophospholipids and acylcarnitine. Integrated multi-omics analysis demonstrated that SEV impaired cognition by suppressing fatty acid oxidation and dysregulating glycerophospholipid metabolism. These findings highlight the critical impact of anesthetic selection in diabetic populations.