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

Overview

1. Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Discussion: 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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE275841, at NCBI GEO; found in “Data availability”

Data Availability Statement

The single-cell RNA-seq and bulk RNA-seq datasets generated in this study have been deposited in the NCBI Gene Expression Omnibus (GEO) under accession numbers GSE275841 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE275841) (scRNA-seq) and GSE275842 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE275842) (bulk RNA-seq), respectively. Processed data underlying the principal figures and tables are included in the article and its supplementary materials. Additional processed data, analysis metadata, and code or parameter information supporting the findings of this study are available from the corresponding author upon reasonable request.

The data presented in this study are deposited in the NCBI Gene Expression Omnibus (GEO) repository, accession numbers GSE275841 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE275841) and GSE275842 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE275842). The single-cell RNA-seq dataset is available under accession number GSE275841 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE275841), and the bulk RNA-seq dataset is available under accession number GSE275842 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE275842). Processed data underlying the main figures and tables are included in the article and Supplementary Material. Additional processed data, analysis metadata, and code or parameter information supporting the findings of this study are available from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Recorded: type, language, journal, volume, pages, dates, 4 authors, 6 keywords, 24 references.

Cite

This paper

Huang, P., Chen, C., Wang, M., & Xue, L. (2026). Decoding neuroimmune ferroptotic vulnerability in isoflurane-induced neonatal neurotoxicity via the SLC7A11/GPX4 axis. Frontiers in pharmacology, 17, 1803172. https://doi.org/10.3389/fphar.2026.1803172

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