Systemic functions of glucocorticoid receptor alpha (GRα) across major organ systems.
| Organ/System | GRα function summary |
|---|---|
| Immune system | Coordinates resolution of inflammation by suppressing NF-κB/AP-1 cytokines, upregulating GILZ/MKP-1/Annexin A1, limiting neutrophil/macrophage survival, and supporting Treg-mediated tolerance [20–22]. |
| Central nervous system | Modulates synaptic plasticity, hippocampal neurogenesis, and stress adaptation; provides negative feedback on the HPA axis to control glucocorticoid levels; influences emotional regulation via MR/serotonin signaling [28]. |
| Peripheral nervous system | Influences autonomic outflow and neuroimmune crosstalk; regulates inflammatory tone and contributes to sensory and metabolic homeostasis under stress [23, 24]. |
| Endocrine system | Controls HPA axis reactivity and feedback; modulates thyroid, gonadal, and growth hormone axes; coordinates stress hormonal signaling across endocrine networks [6, 25]. |
| Cardiovascular and endothelium | Upregulates adrenergic receptors, enhances catecholamine sensitivity and NO production via eNOS; maintains vascular tone, limits inflammation and permeability; regulates sodium-fluid balance [19, 26–32]. |
| Lungs | Suppresses airway inflammation, enhances β2-adrenergic bronchodilation, promotes alveolar repair and surfactant production, reduces vascular leakage in ARDS [33]. |
| Kidneys | Promotes AQP2/ENaC expression to retain sodium/water; limits oxidative stress and inflammation; supports podocyte and epithelial structure under systemic stress [34–36]. |
| Liver | Regulates gluconeogenesis, lipid metabolism, acute-phase proteins; modulates inflammation and circadian-metabolic adaptation; ensures substrate mobilization [6, 37]. |
| Gastrointestinal tract | Enhances barrier integrity via tight junction regulation; modulates gut microbiota composition; and reduces oxidative stress and systemic inflammation via gut immune signaling [6, 38–40]. |
| Pancreas | Regulates insulin/glucagon secretion, controls 11β-HSD1 expression in islets; maintains glucose homeostasis; modulates circadian gene expression in β-cells [41–43]. |
| Adipose tissue | Promotes lipolysis, modulates insulin sensitivity, limits inflammation; preserves mitochondrial function, and regulates adipokines under metabolic stress [44–46]. |
| Muscle | Facilitates protein catabolism during stress adaptation, preserves mitochondrial integrity and glucose metabolism, and regulates oxidative stress and energy utilization [47–49]. |
This table summarizes the systemic functions of GRα across major organ systems, highlighting its integrative role in coordinating physiological stress responses. For a comprehensive recent review, which includes GRα regulation of circulating cells, see [6]. NF-κB: nuclear factor kappa B; AP-1: activator protein-1; GILZ: glucocorticoid-induced leucine zipper; HPA: hypothalamic-pituitary-adrenal; MR: mineralocorticoid receptor; NO: nitric oxide; eNOS: endothelial nitric oxide synthase; ARDS: acute respiratory distress syndrome; AQP: aquaporin; ENaC: epithelial sodium channel.
This work is dedicated to Professor George P. Chrousos’s guidance and mentorship over the past twenty years and to Don Donati, Esq., for his steadfast support of academic freedom and research integrity.
AI-Assisted Work Statement: The content of Table 1 was synthesized from structured evidence obtained via the Consensus research platform and organized with editorial assistance from ChatGPT (OpenAI) to ensure clarity, consistency, and accurate citation. Preparation of the comparative analysis of Tables 2 and 3 was supported by insights derived from Consensus (https://consensus.app), a PubMed-linked AI research synthesis platform used to verify and update biomedical references, and ChatGPT (GPT-5, OpenAI, 2025), which assisted in drafting and formatting the table, integrating reference alignment, and refining academic clarity. Both tools were used exclusively to enhance scientific precision and presentation quality; all final interpretations and conclusions reflect the author’s independent critical analysis. After using the tool/service, author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.
GUM: Conceptualization, Investigation, Methodology, Writing—original draft, Project administration, Writing—review & editing. The author read and approved the submitted version.
The author has no competing interests to declare or any real or perceived financial interest in any product or commodity mentioned in this paper.
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