ArticleEBioMedicine2019
PI3K inhibitors protect against glucocorticoid-induced skin atrophy.
Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 43 citations in OpenAlex.
- A Molecular-Dynamics-Guided Screening Pipeline Identifies Topical Glucocorticoid Receptor Modulators with Selective Epidermal Activation.Skin pharmacology and physiology · 2026Article
- Mosaic partial epidermal reprogramming remodels neighbors and niches to refine skin homeostasis and repair.Nature communications · 2026Article
- Endothelial senescence drives intrinsic skin aging via the neuroimmune CGRP-mast cell axis in mice.Communications biology · 2025Article
- Anti-Cancer Outcome of Glucocorticoid Receptor Transrepression by Synephrine Derivatives in Hematological Malignancies.International journal of molecular sciences · 2025Article
- Glucocorticoid-Mediated Skeletal Muscle Atrophy: Molecular Mechanisms and Potential Therapeutic Targets.International journal of molecular sciences · 2025Review
- The impact of glucocorticoid receptor transactivation on context-dependent cell migration dynamics.Scientific reports · 2025Article
- Synthesis and Anti-Cancer Activity of the Novel Selective Glucocorticoid Receptor Agonists of the Phenylethanolamine Series.International journal of molecular sciences · 2024Article
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- A body shape index (ABSI) is associated inversely with post-menopausal progesterone-receptor-negative breast cancer risk in a large European cohort.BMC cancer · 2023Article
- Characterization of Transcriptomic and Proteomic Changes in the Skin after Chronic Fluocinolone Acetonide Treatment.Biomolecules · 2022Article
- Nutritional Sensor REDD1 in Cancer and Inflammation: Friend or Foe?International journal of molecular sciences · 2022Review
- Autophagy inhibitors alleviate Japanese encephalitis virus-induced cerebral inflammation in mice.Archives of virology · 2022Article
- Reversion of glucocorticoid-induced senescence and collagen synthesis decrease by LY294002 is mediated through p38 in skin.International journal of biological sciences · 2022Article
- The long winding road to the safer glucocorticoid receptor (GR) targeting therapies.Oncotarget · 2022Review
- FKBP51 and the molecular chaperoning of metabolism.Trends in endocrinology and metabolism: TEM · 2021Review
- β-Ionone Attenuates Dexamethasone-Induced Suppression of Collagen and Hyaluronic Acid Synthesis in Human Dermal Fibroblasts.Biomolecules · 2021Article
- Caffeoyl-Prolyl-Histidine Amide Inhibits Fyn and Alleviates Atopic Dermatitis-Like Phenotypes via Suppression of NF-κB Activation.International journal of molecular sciences · 2020Article
- Regulated in Development and DNA Damage Responses 1 Prevents Dermal Adipocyte Differentiation and Is Required for Hair Cycle-Dependent Dermal Adipose Expansion.The Journal of investigative dermatology · 2020Article
- A Novel Approach to Safer Glucocorticoid Receptor-Targeted Anti-lymphoma Therapy via REDD1 (Regulated in Development and DNA Damage 1) Inhibition.Molecular cancer therapeutics · 2020Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundSkin atrophy is a major adverse effect of topical glucocorticoids. We recently reported that REDD1 (regulated in development and DNA damage 1) and FKBP51 (FK506 binding protein 5), negative regulators of mTOR/Akt signaling, are induced by glucocorticoids in mouse and human skin and are central drivers of steroid skin atrophy. Thus, we hypothesized that REDD1/FKBP51 inhibitors could protect skin against catabolic effects of glucocorticoids.
methodsUsing drug repurposing approach, we screened LINCS library (http://lincsproject.org/LINCS/) to identify repressors of REDD1/FKBP51 expression. Candidate compounds were tested for their ability to inhibit glucocorticoid-induced REDD1/FKBP51 expression in human primary/immortalized keratinocytes and in mouse skin. Reporter gene expression, microarray, and chromatin immunoprecipitation were employed to evaluate effect of these inhibitors on the glucocorticoid receptor (GR) signaling.
findingsBioinformatics analysis unexpectedly identified phosphoinositide-3-kinase (PI3K)/mTOR/Akt inhibitors as a pharmacological class of REDD1/FKBP51 repressors. Selected PI3K/mTOR/Akt inhibitors-Wortmannin (WM), LY294002, AZD8055, and two others indeed blocked REDD1/FKBP51expression in human keratinocytes. PI3K/mTOR/Akt inhibitors also modified global effect of glucocorticoids on trascriptome, shifting it towards therapeutically important transrepression; negatively impacted GR phosphorylation; nuclear translocation; and GR loading on REDD1/FKBP51 gene promoters. Further, topical application of LY294002 together with glucocorticoid fluocinolone acetonide (FA) protected mice against FA-induced proliferative block and skin atrophy but did not alter the anti-inflammatory activity of FA in ear edema test.
interpretationOur results built a strong foundation for development of safer GR-targeted therapies for inflammatory skin diseases using combination of glucocorticoids with PI3K/mTOR/Akt inhibitors. FUND: Work is supported by NIH grants R01GM112945, R01AI125366, and HESI-THRIVE foundation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.