Glucocorticoid receptor modulation as a host-directed strategy for inflammatory priming across chronic disease states
10 affiliations
- 1Department of Microbiology, Immunology and Pathology, Colorado State University
- 2Neurodegenerative Disease Research Center, Barrow Neurological Institute
- 3Department of Pathology, NYU Grossman School of Medicine, New York University
- 4Baylor College of Medicine
- 5Department of Neuroscience, Medical University of South Carolina
- 6Van Drie Research LLC
- 7Department of Psychology, University of Kentucky
- 828bio LLC
- 9Pop Test Oncology LLC
- 10Department of Urology, Icahn School of Medicine at Mount Sinai
Abstract
Chronic inflammation is increasingly recognized as a shared feature across neuropsychiatric, neurodegenerative, metabolic, oncologic, and post-infectious disorders, yet treatments mainly target downstream effects. Evidence suggests dysregulated glucocorticoid receptor (GR; encoded by NR3C1 ) signaling may regulate inflammation upstream, linking stress, HPA axis dysfunction, altered neuroimmune signaling, NF-κB activation, and ongoing inflammation. We review evidence supporting selective modulation of GR as a host-directed therapy targeting this shared mechanism. Across experimental systems, GR modulation is associated with attenuation of NF-κB-associated inflammatory signaling while preserving host-defense and repair-associated pathways. Exploratory clinical observations suggest that biological and therapeutic responses may depend on the degree of GR modulation, providing a hypothesis for prospective evaluation of a potential therapeutic window. Despite remaining questions, convergent evidence views dysregulated GR signaling as a promising upstream target across conditions like post-infectious inflammation, neuropsychiatric disorders, addiction, metabolic disease, and some cancers. We propose a biomarker-guided framework to evaluate selective GR modulation to restore the balance of inflammation in patient groups, rather than just suppressing downstream effects.
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BibTeX
@article{slayden2026glucocorticoid,
title = {{Glucocorticoid receptor modulation as a host-directed strategy for inflammatory priming across chronic disease states}},
author = {Richard A. Slayden and Ronald B. Tjalkens and Neil D. Theise and Christopher D. Verrico and Estefania P. Azevedo and John H. Van Drie and Michael T. Bardo and Mark A. Prendergast and Christopher M. Butt and Randice Altschul and Sujit S. Nair and Dimple Chakravarty and Ashutosh K. Tewari},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1931270},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1931270/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Glucocorticoid receptor modulation as a host-directed strategy for inflammatory priming across chronic disease states
AU - Richard A. Slayden
AU - Ronald B. Tjalkens
AU - Neil D. Theise
AU - Christopher D. Verrico
AU - Estefania P. Azevedo
AU - John H. Van Drie
AU - Michael T. Bardo
AU - Mark A. Prendergast
AU - Christopher M. Butt
AU - Randice Altschul
AU - Sujit S. Nair
AU - Dimple Chakravarty
AU - Ashutosh K. Tewari
PY - 2026
DA - 2026/10/19
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1931270
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1931270/full
AB - Chronic inflammation is increasingly recognized as a shared feature across neuropsychiatric, neurodegenerative, metabolic, oncologic, and post-infectious disorders, yet treatments mainly target downstream effects. Evidence suggests dysregulated glucocorticoid receptor (GR; encoded by NR3C1 ) signaling may regulate inflammation upstream, linking stress, HPA axis dysfunction, altered neuroimmune signaling, NF-κB activation, and ongoing inflammation. We review evidence supporting selective modulation of GR as a host-directed therapy targeting this shared mechanism. Across experimental systems, GR modulation is associated with attenuation of NF-κB-associated inflammatory signaling while preserving host-defense and repair-associated pathways. Exploratory clinical observations suggest that biological and therapeutic responses may depend on the degree of GR modulation, providing a hypothesis for prospective evaluation of a potential therapeutic window. Despite remaining questions, convergent evidence views dysregulated GR signaling as a promising upstream target across conditions like post-infectious inflammation, neuropsychiatric disorders, addiction, metabolic disease, and some cancers. We propose a biomarker-guided framework to evaluate selective GR modulation to restore the balance of inflammation in patient groups, rather than just suppressing downstream effects.
SN - 1663-9812
ER -