ORIGINAL RESEARCH article
Front. Neurosci.
Sec. Neurodegeneration
This article is part of the Research TopicMetabolic Implications in Sepsis and Inflammation-related Critical IllnessesView all 7 articles
Glutathione Metabolism as a Key Regulator of Oxidative Hippocampal Injury in Sepsis-Associated Encephalopathy: An Integrated Proteomics and Metabolomics Study
Provisionally accepted
- 1School of Basic Medicine, Ningxia Medical University, Yinchuan, China
- 2The First Clinical Medical College of Ningxia Medical University, Yinchuan, China
- 3Ningxia Medical University School of Basic Medicine, Yinchuan, China
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Sepsis-associated encephalopathy (SAE) is characterized by acute neurological dysfunction and hippocampal damage. Notably, oxidative stress is an important component driving neuronal injury; however, the contribution of dysfunctional glutathione (GSH) metabolism to hippocampal injury in SAE remains to be elucidated. The aim of this research was to elucidate the molecular and biochemical alterations in the hippocampus induced by SAE by integrating proteomics and metabolomics, with the ultimate goal of offering better neuroprotection. A murine model of SAE, established via cecal ligation and puncture (CLP), exhibited pronounced hippocampal damage, microglial activation, and cognitive deficits, alongside elevated pro-inflammatory cytokines as well as oxidative stress markers ROS and MDA. Proteomic analysis identified 156 differentially expressed proteins (DEPs), with glutathione metabolism emerging as the most disrupted pathway. Metabolomic profiling further confirmed systemic glutathione depletion and mitochondrial dysfunction, evidenced by reductions in S-lactoylglutathione, carnitine species, and NAD⁺ intermediates. Multi-omics integration revealed a "high-inflammation, high-oxidation, low-metabolism" triad, predominantly regulated by Stat1–(2-carboxypropyl)-Cysteamine–C3 interactions. Mechanistic validation further confirmed downregulation of Nrf2, HO-1, and GPX4 in CLP mice, directly linking glutathione dysregulation to neuronal apoptosis. Our findings unveil glutathione metabolism as a pivotal hub in SAE pathogenesis, and highlight glutathione-related pathways as mitigating therapeutic targets for oxidative hippocampal injury in SAE.
Keywords: Glutathione metabolism, Hippocampal injury, multi-omics, Oxidative Stress, sepsis-associated encephalopathy
Received: 24 Jul 2025; Accepted: 16 Dec 2025.
Copyright: © 2025 Yanning, nan, Teng, Tao, Wang, Wang, Li and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yin Wang
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