Trial reportBlood2013
Simvastatin and t-butylhydroquinone suppress KLF1 and BCL11A gene expression and additively increase fetal hemoglobin in primary human erythroid cells.
Trial report in Blood, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
21 citing papers in PubMed, 41 citations in OpenAlex.
- Modeling Therapeutic Targets: β-Globin Disorders and Beyond.Advances in experimental medicine and biology · 2026Review
- Innovations in Drug Discovery for Sickle Cell Disease Targeting Oxidative Stress and NRF2 Activation-A Short Review.International journal of molecular sciences · 2025Review
- Review
- Simvastatin-Mediated Nrf2 Activation Induces Fetal Hemoglobin and Antioxidant Enzyme Expression to Ameliorate the Phenotype of Sickle Cell Disease.Antioxidants (Basel, Switzerland) · 2024Article
- Keap1-Nrf2 Heterodimer: A Therapeutic Target to Ameliorate Sickle Cell Disease.Antioxidants (Basel, Switzerland) · 2023Review
- Revisiting fetal hemoglobin inducers in beta-hemoglobinopathies: a review of natural products, conventional and combinatorial therapies.Molecular biology reports · 2022Review
- Targeting IFN-γ-inducible lysosomal thiol reductase overcomes chemoresistance in AML through regulating the ROS-mediated mitochondrial damage.Translational oncology · 2021Article
- NRF2 mediates γ-globin gene regulation through epigenetic modifications in a β-YAC transgenic mouse model.Experimental biology and medicine (Maywood, N.J.) · 2020Article
- BCL11A: a potential diagnostic biomarker and therapeutic target in human diseases.Bioscience reports · 2019Review
- δ-Aminolevulinate induces fetal hemoglobin expression by enhancing cellular heme biosynthesis.Experimental biology and medicine (Maywood, N.J.) · 2019Article
- Mechanisms of NRF2 activation to mediate fetal hemoglobin induction and protection against oxidative stress in sickle cell disease.Experimental biology and medicine (Maywood, N.J.) · 2019Review
- Article
- Detecting genome-wide directional effects of transcription factor binding on polygenic disease risk.Nature genetics · 2018Article
- Complementary and alternative medicine use in thalassemia patients in Shiraz, southern Iran: A cross-sectional study.Journal of traditional and complementary medicine · 2018Article
- Cis-vaccenic acid induces differentiation and up-regulates gamma globin synthesis in K562, JK1 and transgenic mice erythroid progenitor stem cells.European journal of pharmacology · 2016Article
- Therapeutic fetal-globin inducers reduce transcriptional repression in hemoglobinopathy erythroid progenitors through distinct mechanisms.Blood cells, molecules & diseases · 2016Article
- Phase 1 Study of a Sulforaphane-Containing Broccoli Sprout Homogenate for Sickle Cell Disease.PloS one · 2016Article
- An international effort to cure a global health problem: A report on the 19th Hemoglobin Switching Conference.Experimental hematology · 2015Review
- Cell signaling pathways involved in drug-mediated fetal hemoglobin induction: Strategies to treat sickle cell disease.Experimental biology and medicine (Maywood, N.J.) · 2015Review
- Evaluation of lovastatin effects on expression of anti-apoptotic Nrf2 and PGC-1α genes in neural stem cells treated with hydrogen peroxide.Molecular neurobiology · 2014Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
unlabelledAlthough increased fetal hemoglobin (HbF) levels have proven benefit for people with β-hemoglobinopathies, all current HbF-inducing agents have limitations. We previously reported that drugs that activate the NRF2 antioxidant response signaling pathway increase HbF in primary human erythroid cells. In an attempt to increase HbF levels achieved with NRF2 activators, in the present study, we investigated potential complementary activity between these agents and HMG-CoA reductase inhibitors (statins) based on their ability to induce KLF2 protein levels. Experiments in K562 cells showed that simvastatin increased KLF2 mRNA and protein and KLF2 binding to HS2 of the β-globin locus control region and enhanced -globin mRNA production by the NRF2 activator Tert-butylhydroquinone (tBHQ). When tested in differentiating primary human erythroid cells, simvastatin induced HbF alone and additively with tBHQ, but it did not increase KLF2 mRNA or locus control region binding above levels seen with normal differentiation. Investigating alternative mechanisms of action, we found that both simvastatin and tBHQ suppress β-globin mRNA and KLF1 and BCL11A mRNA and protein, similar to what is seen in people with an HPFH phenotype because of KLF1 haploinsufficiency. These findings identify statins as a potential class of HbF-inducing agents and suggest a novel mechanism of action based on pharmacologic suppression of KLF1 and BCL11A gene expression. KEY POINTS: Simvastatin and tBHQ suppress KLF1 and BCL11 gene expression and additively increase fetal hemoglobin in primary human erythroid cells. Because both drugs are FDA-approved, these findings could lead to clinical trials in the relatively near future.
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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.