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Antioxidants
Volume 14
Issue 12
10.3390/antiox14121395
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

ROS-Driven STAT1 S-Glutathionylation Sustains IFNγ Signaling and Pro-Inflammatory Microglial Polarization

by
Martina Brattini
,
Alessandra Carcereri de Prati
,
Carlotta Passarini
,
Marta Menegazzi
,
Alessandra Fiore
,
Maria Mosaico
,
Michelle D’Urso
,
Sofia Mariotto
* and
Elena Butturini
Neurosciences, Biomedicine and Movement Sciences, Biological Chemistry Section, University of Verona, Strada le Grazie 8, 37129 Verona, Italy
*
Author to whom correspondence should be addressed.
Antioxidants 2025, 14(12), 1395; https://doi.org/10.3390/antiox14121395 (registering DOI)
Submission received: 16 October 2025 / Revised: 21 November 2025 / Accepted: 21 November 2025 / Published: 23 November 2025
(This article belongs to the Special Issue Redox Regulation in Inflammation and Disease—3rd Edition)
Versions Notes

Abstract

Oxidative stress is a major driver of neuroinflammation, yet the molecular redox mechanisms that shape microglial activation remain incompletely defined. Among reversible redox modifications, protein S-glutathionylation has emerged as a key regulator of signaling cascades under conditions of elevated Reactive Oxygen Species (ROS). While IFNγ is known to activate STAT1 and promote a pro-inflammatory microglial phenotype, the contribution of oxidative stress to this process is poorly understood. Here, we investigated the interplay between ROS and STAT1 signaling in IFNγ-stimulated microglial cells. We demonstrate that ROS not only enhance STAT1 phosphorylation but also promote its S-glutathionylation, a modification that sustains STAT1 transcriptional activity. This dual regulation leads to prolonged expression of pro-inflammatory mediators, including iNOS, COX2, TNFα, and IL-6. Importantly, STAT1-deficient cells fail to mount these responses, confirming STAT1 as a central redox-sensitive hub in microglial polarization. Our findings identify S-glutathionylation as a molecular switch that links oxidative stress to persistent STAT1 activation and M1 polarization. These results suggest that targeting STAT1 redox regulation could help control microglial overactivation and may offer new opportunities for therapeutic intervention in neuroinflammatory and neurodegenerative diseases.
Keywords: IFNγ; STAT1; S-glutathionylation; ROS; neuroinflammation IFNγ; STAT1; S-glutathionylation; ROS; neuroinflammation

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MDPI and ACS Style

Brattini, M.; Carcereri de Prati, A.; Passarini, C.; Menegazzi, M.; Fiore, A.; Mosaico, M.; D’Urso, M.; Mariotto, S.; Butturini, E. ROS-Driven STAT1 S-Glutathionylation Sustains IFNγ Signaling and Pro-Inflammatory Microglial Polarization. Antioxidants 2025, 14, 1395. https://doi.org/10.3390/antiox14121395

AMA Style

Brattini M, Carcereri de Prati A, Passarini C, Menegazzi M, Fiore A, Mosaico M, D’Urso M, Mariotto S, Butturini E. ROS-Driven STAT1 S-Glutathionylation Sustains IFNγ Signaling and Pro-Inflammatory Microglial Polarization. Antioxidants. 2025; 14(12):1395. https://doi.org/10.3390/antiox14121395

Chicago/Turabian Style

Brattini, Martina, Alessandra Carcereri de Prati, Carlotta Passarini, Marta Menegazzi, Alessandra Fiore, Maria Mosaico, Michelle D’Urso, Sofia Mariotto, and Elena Butturini. 2025. "ROS-Driven STAT1 S-Glutathionylation Sustains IFNγ Signaling and Pro-Inflammatory Microglial Polarization" Antioxidants 14, no. 12: 1395. https://doi.org/10.3390/antiox14121395

APA Style

Brattini, M., Carcereri de Prati, A., Passarini, C., Menegazzi, M., Fiore, A., Mosaico, M., D’Urso, M., Mariotto, S., & Butturini, E. (2025). ROS-Driven STAT1 S-Glutathionylation Sustains IFNγ Signaling and Pro-Inflammatory Microglial Polarization. Antioxidants, 14(12), 1395. https://doi.org/10.3390/antiox14121395

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