# Glutathione metabolism as a key regulator of oxidative hippocampal injury in sepsis-associated encephalopathy: an integrated proteomics and metabolomics study

## TL;DR

This study shows that disrupted glutathione metabolism plays a key role in brain damage caused by sepsis, offering new targets for treatment.

## Contribution

The study identifies glutathione metabolism as a central regulator of oxidative injury in sepsis-associated encephalopathy through integrated proteomics and metabolomics.

## Key findings

- Glutathione metabolism is the most disrupted pathway in hippocampal injury during sepsis.
- Reduced Nrf2, HO-1, and GPX4 expression links glutathione dysregulation to neuronal apoptosis.
- A 'high-inflammation, high-oxidation, low-metabolism' triad is regulated by a specific interaction axis.

## Abstract

Sepsis-associated encephalopathy (SAE) is characterized by acute neurological dysfunction and hippocampal damage, with oxidative stress being a key driver of neuronal injury. However, the role of dysfunctional glutathione (GSH) metabolism in hippocampal injury during SAE remains unclear. This study aimed to clarify the molecular and biochemical changes in the hippocampus induced by SAE through multi-omics integration (proteomics and metabolomics), thereby providing a theoretical basis for improved neuroprotective strategies.

A murine SAE model was established via cecal ligation and puncture (CLP). Subsequent analyses included assessments of hippocampal tissue damage, microglial activation, and cognitive function in mice. Levels of pro-inflammatory cytokines, reactive oxygen species (ROS), and malondialdehyde (MDA) (oxidative stress markers) were detected. Proteomic analysis was performed to identify differentially expressed proteins (DEPs), while metabolomic profiling was used to characterize metabolic changes. Multi-omics integration was conducted to reveal core regulatory networks, and mechanistic validation focused on the expression of Nrf2, HO-1, and GPX4.

The CLP-induced SAE model showed significant hippocampal damage, microglial activation, cognitive deficits, and increased levels of pro-inflammatory cytokines, ROS, and MDA. Proteomic analysis identified 156 DEPs, with glutathione metabolism being the most severely disrupted pathway. Metabolomic results confirmed systemic glutathione depletion and mitochondrial dysfunction, as evidenced by reduced levels of S-lactoylglutathione, carnitine species, and NAD+ intermediates. Multi-omics integration revealed a “high-inflammation, high-oxidation, low-metabolism” triad, which is mainly regulated by the Stat1-(2-carboxypropyl)-Cysteamine-C3 interaction axis. Mechanistic validation further confirmed downregulated expression of Nrf2, HO-1, and GPX4 in CLP mice, establishing a direct link between glutathione dysregulation and neuronal apoptosis.

Our findings demonstrate that glutathione metabolism serves as a pivotal hub in the pathogenesis of SAE. The identified glutathione-related pathways provide potential therapeutic targets for alleviating oxidative stress-induced hippocampal injury in SAE, offering new insights for the clinical management of SAE-related neurological damage.