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Non-genomic Effects of Glucocorticoids: An Updated View
Open accessAbstract
Glucocorticoid (GC) anti-inflammatory effects generally require a prolonged onset of action and involve genomic processes. Because of the rapidity of some of the GC effects, however, the concept that non-genomic actions may contribute to GC mechanisms of action has arisen. While the mechanisms have not been completely elucidated, the non-genomic effects may play a role in the management of inflammatory diseases. For instance, we recently reported that GCs 'rapidly' enhanced the effects of bronchodilators, agents used in the treatment of allergic asthma. In this review article, we discuss (i) the non-genomic effects of GCs on pathways relevant to the pathogenesis of inflammatory diseases and (ii) the putative role of the membrane GC receptor. Since GC side effects are often considered to be generated through its genomic actions, understanding GC non-genomic effects will help design GCs with a better therapeutic index.
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“suggesting that also the effects on synaptic transmission in the CeA are mediated via non-genomic GR signaling.”
From Alcohol dependence and withdrawal increase sensitivity of central amygdalar GABAergic synapses to the glucocorticoid receptor antagonist mifepristone in male rats (2022) · cites this paper as Panettieri et al., 2019
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“most non-genomic glucocorticoid effects are sensitive to mifepristone antagonism (Panettieri et al., 2019)”
From Alcohol dependence and withdrawal increase sensitivity of central amygdalar GABAergic synapses to the glucocorticoid receptor antagonist mifepristone in male rats (2022) · cites this paper as Panettieri et al., 2019
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Wan, D., Lu, T., Li, C., & Hu, C. (2024) · Journal of Neuroscience · doi:10.1523/jneurosci.0179-24.2024 · Cited by 1
Nrf2: A Promising Therapeutic Target for Glucocorticoid-Resistant Chronic Rhinosinusitis
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New strategy for glucocorticoid use in systemic lupus erythematosus
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“Процессы трансгрес-сии и трансактивации тесно связаны между собой – так, что токсичность ГК увеличивается параллельно с проти-вовоспалительным действием по мере того, как геном-ный путь становится более активным [18].”
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“10 As the dose of GC administered increases, the degree to which the genomic pathway is activated decreases, and that of its non-genomic counterpart increases.”
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“By binding to the intracellular glucocorticoid receptor (GR), GCs exert widespread genomic and non-genomic effects, influencing inflammatory signaling pathways, cardiovascular regulation, and neuroendocrine activity (Panettieri et al. 2019).”
Wen, B., Wu, X., Ma, X., Li, D., & Qian, L. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1830573 · Cited by 2
“…and non-genomic mechanisms: the hormone-receptor complex enters the nucleus to regulate the transcription of in fl ammation-related genes, inhibiting in fl ammatory cell activity and the production of in fl ammatory factors; they can also rapidly reduce vascular permeability and exudation (5, 6).”
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Giachetti, N., Hadjadj, J., Gaudre, N., Lavigne, C., & Lacombe, V. (2026) · Rheumatology International · doi:10.1007/s00296-026-06130-3 · Cited by 1
“Non-genomic GC effects, such as mitochondrial destabilization and activation of apoptotic pathways [41, 43 ], might directly affect clonal cells or indi - rectly reduce clonal selection by modulating the inflamma - tory bone marrow niche [44 ].”
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“They primarily function by activating glucocorticoid receptors (GRs), which produces anti-inflammatory and immunosuppressive effects while also modulating neuronal activity in the hippocampus [56,57].”
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Bacinschi, N., Catcov, C., Chişlari, S., Guţu, I., & Covalschi, T. (2022) · Farmacist ro · doi:10.26416/farm.206.3.2022.6521 · Cited by 1
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The Role of Steroids in Performing Voice
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“given what has typically been described for the time to onset of action and underscores more recent evidence showing that steroid effects may begin within minutes of administration.(2) The timing of the steroid therapy is of interest because it may parallel hormonal changes expected in the fetal milieu during labor.”
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COVID-19 HASTALARINDA KORTİKOSTEROİD TEDAVİSİ: NE ZAMAN VE NASIL?
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“Rapid effects of glucocorticoids in mammals, birds and amphibians have been attributed to non-genomic receptors, possibly in cell membranes, that generate behavioral and physiological responses to environmental perturbations (Panettieri et al., 2019).”
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Keller, F. C., Kočí, V., Řiháková, K., Maláska, J., & Stašek, J. (2021) · Anesteziologie a intenzivní medicína · doi:10.36290/aim.2021.036
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“La vía no genómica, a diferencia de la anterior, tiene un inicio de acción más rápido, un efecto antiinflamatorio más potente y se relaciona con menores efectos adversos, debido en parte a que su efecto es transitorio((41,42)).”
Adcock, I. M., & Mumby, S. E. (2021) · Springer eBooks · doi:10.1007/978-3-030-57401-7_67
Utilizarea glucocorticoizilor în infecția cu SARS CoV 2: pro și contra
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“гранулоцитів, запальну активацію макрофагів, дегрануляцію тучних клітин, впливають на іонні канали епітеліальних клітин бронхів [6].”
Visceral extra‐abdominal panniculitis after COVID19
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“Corticosteroids are known to have genomic as well as nongenomic effects that involve different mechanisms of action (11).”
Honour, J. W. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-818124-9.00008-5
Glucocorticoid Therapy in Oncology
Flory, A. (2023) · CABI eBooks · doi:10.1079/9781789245820.0013
Effect of ACTH Stimulation on Ischemia-Modified Albumin Levels in vivo
Şahin, N. M., Esen, S., Erdeve, Ş. S., Neşeli̇oğlu, S., Erel, Ö., & Çetinkaya, S. Ç. (2023) · Journal of Clinical Research in Pediatric Endocrinology · doi:10.4274/jcrpe.galenos.2023.2023-5-22
“Studies have shown that glucocorticoids have rapid, non-genomic effects on ROS formation via the generation of intracellular second messengers and signal transduction cascades (22-24).”
BackgroundQuarde, A. (2023) · doi:10.1002/9781119863564.ch1
Uji Aktivitas Anti-Inflamasi Infusa Bunga Pukul Empat (Mirabilis jalapa L.) secara In Vivo
Handayani, E., Hasina, R., Zakiah, M. P., Suryani, B., Erlangga, I. B. P., & Radiartini, N. N. (2023) · Unram Medical Journal · doi:10.29303/jk.v12i2.4355
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Dexamethasone weakens the respiratory effects of pro-inflammatory cytokine TNF-α in rat
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Rella, V., Rotondo, C., Barile, R., Erroi, F., Cantatore, F. P., & Corrado, A. (2024) · Hospital Practice · doi:10.1080/21548331.2024.2423598
“GCs act through several mechanisms which can be mainly distinguished in genomic and non-genomic ones [8,28].”
InfluentialFazio, E., Bionda, A., Attard, G., Medica, P., Fauci, D. L., Amato, A., Liotta, L., & Lopreiato, V. (2024) · Animals · doi:10.3390/ani14223336 · Cited by 4
“A key mode of action for the rapid physiological effects of glucocorticoids involves changes in Ca ++ concentrations [44,45], and studies have shown that this steroid either stimulates or inhibits basal Ca ++ levels in a tissue-specific manner [46,47].”
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“…to rapidly activate intracellular signaling cascades such as ERK/MAPK, PI3K/AKT, and CaMKII/CREB pathways, modulating synaptic plasticity, cellular excitability, and emotional regulation (Chen et al., 2012; Evanson et al., 2010; Groeneweg et al., 2011; Langer et al., 2025; Panettieri et al., 2019).”
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Hanus, P., Frydecka, D., & Ślęzak, M. (2026) · Journal of Neurochemistry · doi:10.1111/jnc.70394 · Cited by 1
“Cytoplasmic actions of GCs are mediated by the activation of intracellular signaling cascades, such as PI3K/Akt, MAPK/ERK or G-protein coupled pathways, with effects varying by cell type (Panettieri et al. 2019).”
InfluentialGenome-wide analyses of signaling pathways controlled by steroid receptors
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Maladie de Huntington : huntingtine, connectivité neuronale et métabolisme oxydatif
Capellano, L. (2025) · theses.fr (ABES) · doi:10.70675/dd0b8f65z490fz446fz8d1azd0dd5619a044
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Glucocorticoids modulate drug transporter function in human fetal brain endothelial cells
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SKOLNIK, N., Stieritz, J., Akers, J. M., Hudd, T. R., Wright, W. L., Gilbert, I., YUSUFOVA, N., Cook, B., Robb, E., & Naddaf, H. (2026) · Frontiers in Medicine · doi:10.3389/fmed.2026.1826737
“…delayed anti-inflammatory actions of ICS therapy underpin its role not only in long-term control but also as a first-line response strategy during symptom worsening, interrupting the inflammatory cascade before it escalates and potentially altering the course of an impending exacerbation (69, 73).”
New insights on anticancer glucocorticoid receptor modulators: a patent review (2020-present)
Franzin, M., Lucafò, M., Curci, D., Decorti, G., & Stocco, G. (2026) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2026.2689602
“…genomic actions, which typically require hours to manifest, glucocorticoids can also induce rapid, non-genomic effects mediated by cytosolic or membrane-associated GR and by interactions with intracellular signaling pathways, contributing to acute hemodynamic and immunomodulatory responses [39].”
Dexamethason zur perioperativen Analgesie
Pantke, S., Leffler, A., & Eberhardt, M. J. (2026) · AINS - Anästhesiologie · Intensivmedizin · Notfallmedizin · Schmerztherapie · doi:10.1055/a-2754-3503
Chisupa, C. O., & Manchishi, S. M. (2026) · Neuroendocrinology · doi:10.1159/000553326 · Cited by 1
“In addition to genomic signalling described above, non-genomic glucocorticoid signalling is mediated by plasma membrane-bound GRs, particularly within the hypothalamic-pituitary-gonadal (HPG) axis [54], further discussed in (The HPG Axis).”
He, Y., Zhou, Z., Wei, X., Su, N., Yang, T., Wang, K., Yushan, L., Li, X., Hu, X., & Fu, Y. (2026) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2026.07.013
Corticosteroid therapy for drug-induced liver injury: Mind the gap!
Aithal, G. P., Weber, S., & Franks, H. (2026) · Journal of Hepatology · doi:10.1016/j.jhep.2026.07.023
Jancic, P., Kovac, I., Demirtas, H. E., Knežević, N. N., & Lubinsky, G. T. (2026) · Biomolecules · doi:10.3390/biom16081183
“Upon glucocorticoid binding, GR-associated proteins such as heat shock proteins (HSPs) and Src kinase are released, activating downstream signaling cascades [18,21].”
Cohen, L., Tiwari, V., Tesser, J., & Bergman, M. J. (2026) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2026.2718746
Ma, X., Zhang, Y., Xu, M., Dong, Y., & Tang, X. (2026) · ChemistrySelect · doi:10.1002/slct.74247
Khalid, A., Flesher, S., & Shehan, T. S. M. (2026) · Frontiers in Pediatrics · doi:10.3389/fped.2026.1925971
“The comparable effectiveness of low-and high-dose dexamethasone can be explained by glucocorticoid pharmacology and croup pathophysiology (23).”
Hu, B., Gutty, V. S. R., Herzog, R. W., & Duan, D. (2026) · Frontiers in Medicine · doi:10.3389/fmed.2026.1930231
“…exert broad anti-inflammatory effects through multiple mechanisms, including inhibition of vasodilation and vascular permeability, alteration of leukocyte trafficking, suppression of pro-inflammatory genes, upregulation of anti-inflammatory cytokines, and downregulation of TLR expression (208–211).”
Shen, Y.-Q., Tai, Y., Liu, X.-Z., Li, Y., Zhao, Z.-H., Jin, X.-J., & Ma, J. (2026) · Cells · doi:10.3390/cells15171574
“Besides genomic effects [156], glucocorticoids also exert non-genomic effects that may influence mitochondrial function [157,158].”
Acute exacerbation of native lung pulmonary fibrosis immediately after single-lung transplantation
Bando, T., Ryo, T., Sakamoto, K., Imamura, Y., Nakanishi, K., Nakamura, S., Mori, Y., Ando, A., Chen-Yoshikawa, T. F., & Ishii, M. (2026) · JTCVS Open · doi:10.1016/j.xjon.2026.102091
Raise‐Abdullahi, P., Rezamohammadi, F., Rahmani, M., Vafaei, A. A., Pakdel, R., Rashidipour, H., & Rashidy‐Pour, A. (2026) · Addiction Biology · doi:10.1111/adb.70185
“Classical genomic versus rapid corticosteroid signalling: Corticosterone can act through classical intracellular MR/ GR-mediated transcription, but corticosteroids also produce rapid, non-genomic effects on neuronal signalling and neurotransmitter function [57–59].”
Non-Biologic Injections in Sports Medicine
Grusky, A. Z., Hatamiya, N. S., Berrigan, W. A., & Ramirez, F. D. (2026) · Current Reviews in Musculoskeletal Medicine · doi:10.1007/s12178-026-10057-4
Architect or Destroyer: The Diversity of Glucocorticoid Receptor Signaling Pathways in the Brain
Shkarina, L. N., Khaybullina, R., Primak, A. L., Дмитриевич, Б. К., Станиславович, Д. С., & Karagyaur, M. N. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27209027
“In addition, besides the possibility of direct activation of downstream intracellular signaling pathways, a number of studies point to cooperation between mGRs and GPCRs [89,95].”
InfluentialPathogenesis of steroid refractoriness in acute graft versus host disease
Debes, M. S., Ali, S. M., Abouzeid, M., Aljrad, M., & Elyasaky, A. (2026) · Molecular Biology Reports · doi:10.1007/s11033-026-12935-z
“Under inflammatory stress, induced nitric oxide synthase (iNOS) is upregulated with significant rise of NO levels [ 8, 11].”
Metadata
- Authors
- Panettieri, R. A., Schaafsma, D., Amrani, Y., Koziol-White, C., Ostrom, R., & Tliba, O.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- NIHR Leicester Respiratory Biomedical Research Unit (GB)
- Chapman University (US)
- Long Island University (US)
- Corresponding author
- Tliba, Omar
- Venue
- Trends in Pharmacological Sciences
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 40
- Issue
- 1
- Pages
- 38-49
- ISSN
- 0165-6147 (ISSN-L)
- PMC
- PMC7106476
- OpenAlex
- W2902671349
- Cited by
- 297
- References
- 68
- Citations by year
- 2026: 33 · 2025: 42 · 2024: 38 · 2023: 54 · 2022: 47 · 2021: 43 · 2020: 24 · 2019: 16
- FWCI
- 2.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Trends in Pharmacological Sciences (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Chapman University Digital Commons (Chapman University) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (7R01HL111541-07, 2P01HL114471-06, GM107094)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- glucocorticoids, non-genomic effects, anti-inflammatory mechanism, rapid onset of action, bronchodilators, allergic asthma, inflammatory diseases, glucocorticoid adverse effects, therapeutic index
- MeSH terms
- Animals, Anti-Inflammatory Agents, Glucocorticoids, Humans, Inflammation, Receptors, Glucocorticoid, Genomics
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