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

## TL;DR

This study shows that sevoflurane worsens cognitive issues in diabetic mice by disrupting lipid metabolism, while propofol does not have the same effect.

## Contribution

The study reveals a novel mechanism by which sevoflurane exacerbates cognitive dysfunction in diabetes through lipid metabolism disruption.

## Key findings

- Sevoflurane significantly worsened spatial memory and learning in diabetic mice.
- Sevoflurane uniquely disrupted fatty acid metabolism pathways compared to propofol.
- Sevoflurane caused elevated free fatty acids and reduced lysophospholipids in the hippocampus.

## Abstract

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.

The online version contains supplementary material available at 10.1038/s41598-026-37737-y.