Glucocorticoid receptor modulation as a host-directed strategy for inflammatory priming across chronic disease states.

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.