Mesenchymal responses are an essential aspect of tissue repair. Failure to terminate this repair process correctly, however, results in fibrosis and organ dysfunction. Therapies that block fibrosis and restore tissue homeostasis are not yet available for clinical use. Here we characterize the nuclear receptor NR4A1 as an endogenous inhibitor of transforming growth factor-β (TGF-β) signaling and as a potential target for anti-fibrotic therapies. NR4A1 recruits a repressor complex comprising SP1, SIN3A, CoREST, LSD1, and HDAC1 to TGF-β target genes, thereby limiting pro-fibrotic TGF-β effects. Even though temporary upregulation of TGF-β in physiologic wound healing induces NR4A1 expression and thereby creates a negative feedback loop, the persistent activation of TGF-β signaling in fibrotic diseases uses AKT- and HDAC-dependent mechanisms to inhibit NR4A1 expression and activation. Small-molecule NR4A1 agonists can overcome this lack of active NR4A1 and inhibit experimentally-induced skin, lung, liver, and kidney fibrosis in mice. Our data demonstrate a regulatory role of NR4A1 in TGF-β signaling and fibrosis, providing the first proof of concept for targeting NR4A1 in fibrotic diseases.

] Department of Internal Medicine 3 University of Erlangen Nuremberg Erlangen Germany [2] Institute of Rheumatology and Department of Rheumatology 1st Faculty of Medicine Charles University Prague Czech Republic

] Division of Molecular Immunology Department of Internal Medicine 3 Nikolaus Fiebiger Centre University of Erlangen Nuremberg Erlangen Germany [2] Division of Biological Chemistry Medical University Innsbruck Innsbruck Austria

Center for Research of Systemic Autoimmune Diseases University Hospital Zurich Zurich Switzerland

Department of Internal Medicine 3 University of Erlangen Nuremberg Erlangen Germany

Division of Molecular Immunology Department of Internal Medicine 3 Nikolaus Fiebiger Centre University of Erlangen Nuremberg Erlangen Germany

Institut de Génétique et de Biologie Moléculaire et Cellulaire CNRS UMR7104 INSERM U 964 Université de Strasbourg Illkirch France

Nat Rev Drug Discov. 2015 Mar;14(3):163. doi: 10.1038/nrd4559. PubMed

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