Decoding neuroimmune ferroptotic vulnerability in isoflurane-induced neonatal neurotoxicity via the SLC7A11/GPX4 axis

Early-life exposure to general anesthetics has been associated with increased neurodevelopmental vulnerability, but the cell type-resolved mechanisms remain incompletely understood. Here, we investigated whether isoflurane-induced neonatal neurotoxicity is associated with a glia-linked ferroptotic susceptibility state involving altered SLC7A11/GPX4 antioxidant defense signaling.

By integrating single-cell and bulk transcriptomic profiling with in vivo behavioral, histological, and biochemical phenotyping, we identified glia-enriched transcriptional changes associated with inflammatory activation, impaired cystine-glutathione metabolism, and increased lipid peroxidation. In primary neonatal astrocytes, isoflurane induced ferroptosis-related phenotypes accompanied by axis suppression, redox imbalance, and lipid peroxidation, which were partially attenuated by pharmacological rescue. Additional inflammatory challenge and neutralization experiments further showed that immune-associated signaling functionally contributes to suppression of the astrocytic SLC7A11/GPX4 defense axis. Pathway-comparison rescue experiments further indicated that ferroptosis-directed intervention more effectively improved lipid peroxidation-associated injury readouts, whereas apoptosis-directed intervention more strongly reduced caspase-associated changes.

Isoflurane exposure was accompanied by neurodevelopmental and behavioral impairments, reduced expression of SLC7A11/GPX4 axis components, increased lipid oxidative damage, and enhanced neuroimmune reactivity, with convergent data suggesting that astrocytes are an important cellular contributor to this injury-associated state.

Together, these findings support a glia-associated neuroimmune ferroptotic vulnerability framework in isoflurane-induced neonatal neurotoxicity and identify the SLC7A11/GPX4 axis as a candidate mechanism warranting further causal investigation in peri-anesthetic neuroprotection for the developing brain.