Abstract
Sevoflurane's potential impact on cognitive function and neurodevelopment, especially in susceptible populations such as infants and the elderly, has raised widespread concern. This study focuses on how sevoflurane induces ferroptosis in astrocytes and identifies solute carrier family 7 member 11 (SLC7A11) as a mediator of ferroptosis, providing new insights into sevoflurane-related neurotoxic pathways. We analysed single-cell sequencing (scRNA-seq) data from sevoflurane-exposed mice and control mice, supplemented with bulk RNA-seq data, to assess gene expression alterations. Additionally, pregnant mice were subjected to in vivo experiments, and in vitro studies using U251 astrocytoma cells were conducted to evaluate sevoflurane's neurotoxic effects on offspring, focusing on ferroptosis markers and SLC7A11 expression. Sevoflurane exposure led to learning, memory and behavioural deficits in offspring, associated with decreased SLC7A11 expression and increased signs of ferroptosis. In U251 cells, sevoflurane reduced cell viability, increased reactive oxygen species (ROS) levels and affected the expression of ferroptosis regulatory factors, supporting the hypothesis that sevoflurane induces astrocyte ferroptosis through SLC7A11 modulation. Molecular docking experiments suggest a direct interaction between sevoflurane and SLC7A11. This study provides mechanistic insights into sevoflurane-induced neurotoxicity, emphasising the importance of SLC7A11 in regulating astrocyte ferroptosis. Our findings highlight the potential for targeting ferroptosis pathways to mitigate the adverse effects of sevoflurane anaesthesia.