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Nrf2 Regulates Basal Glutathione Production in Astrocytes

He, Jiali, Hewett, Sandra J.·2025·International Journal of Molecular Sciences
DOI 10.3390/ijms26020687PMC PMC11765531
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Abstract

Astrocytes produce and export glutathione (GSH), an important thiol antioxidant essential for protecting neural cells from oxidative stress and maintaining optimal brain health. While it has been established that oxidative stress increases GSH production in astrocytes, with Nrf2 acting as a critical transcription factor regulating key components of the GSH synthetic pathway, the role of Nrf2 in controlling constitutive GSH synthetic and release mechanisms remains incompletely investigated. Our data show that naïve primary mouse astrocytes cultured from the cerebral cortices of Nrf2 knockout (Nrf2−/−) pups have significantly less intracellular and extracellular GSH levels when compared to astrocytes cultured from Nrf2 wild-type (Nrf2+/+) pups. Key components of the GSH synthetic pathway, including xCT (the substrate-specific light chain of the substrate-importing transporter, system xc−), glutamate-cysteine ligase [catalytic (GCLc) and modifying (GCLm) subunits], were affected. To wit: qRT-PCR analysis demonstrates that naïve Nrf2−/− astrocytes have significantly lower basal mRNA levels of xCT and both GCL subunits compared to naïve Nrf2+/+ astrocytes. No change in mRNA levels of glutathione synthetase (GS) or the GSH exporting transporter, Mrp1, was found. Western blot analysis reveals reduced protein levels of both subunits of GCL, while (seleno)cystine uptake into Nrf2−/− astrocytes was reduced compared to Nrf2+/+ astrocytes, confirming decreased system xc− activity. These findings suggest that Nrf2 regulates the basal production of GSH in astrocytes through constitutive transcriptional regulation of GCL and xCT.

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  • The temporal pattern of NRF2 and SOD reflects activation of the Nrf2-ARE axis, which promotes transcription of antioxidant enzymes and restores redox balance.

    “We propose that this temporal pattern reflects activation of the nuclear factor erythroid 2‐related factor 2‐antioxidant response element (Nrf2‐ARE) axis, which promotes the transcription of antioxidant enzymes and restores redox balance (Sigfridsson et al. 2018; He and Hewett 2025).”

    From LDL Cholesterol Modulates Astrocyte Metabolism, Lipid Handling, and Morphology: Evidence From In Vitro and In Vivo Models (2026) · cites this paper as He and Hewett 2025

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Metadata

Authors
He, J., & Hewett, S. J.
Affiliations
Program in Neuroscience, Department of Biology, Syracuse University, Syracuse, NY 13210, USA
ORCID
Hewett, Sandra J.
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2025-01-15
Volume
26
Issue
2
Pages
687
ISSN
1422-0067
DOI
10.3390/ijms26020687
PMC
PMC11765531
Cited by
25
References
6
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
National Institute of Neurological Disorders and Stroke (R01 NS051445)

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