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Updated: Apr 18, 2026

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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Orphan nuclear receptor NR4A1 regulates transforming growth factor-β signaling and fibrosis

Katrin Palumbo-Zerr1, Pawel Zerr1, Alfiya Distler1

  • 1Department of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany.

Nature Medicine
|January 13, 2015
PubMed

Insights

Nuclear receptor NR4A1 inhibits transforming growth factor-β (TGF-β) signaling, offering a new target for anti-fibrotic therapies. NR4A1 agonists show promise in treating fibrosis across multiple organs.

Area of Science:

  • Cellular Biology
  • Molecular Medicine
  • Pathology

Background:

  • Mesenchymal responses are crucial for tissue repair but can lead to fibrosis if unresolved.
  • Current therapies lack the ability to halt fibrosis and restore tissue homeostasis.
  • Transforming growth factor-β (TGF-β) signaling plays a key role in fibrotic processes.

Purpose of the Study:

  • To identify endogenous inhibitors of TGF-β signaling.
  • To explore the therapeutic potential of targeting the nuclear receptor NR4A1 for anti-fibrotic strategies.

Main Methods:

  • Characterization of NR4A1's role in TGF-β signaling.
  • Investigating NR4A1's recruitment of repressor complexes (SP1, SIN3A, CoREST, LSD1, HDAC1).
  • Assessing the efficacy of small-molecule NR4A1 agonists in mouse models of fibrosis.

Main Results:

  • NR4A1 acts as an endogenous inhibitor of TGF-β signaling by recruiting a repressor complex to TGF-β target genes.
  • Persistent TGF-β signaling in fibrosis inhibits NR4A1 expression and activation via AKT and HDAC pathways.
  • NR4A1 agonists effectively inhibited experimental fibrosis in skin, lung, liver, and kidney in mice.

Conclusions:

  • NR4A1 is a key regulator of TGF-β signaling and fibrosis.
  • Targeting NR4A1 represents a novel therapeutic approach for fibrotic diseases.
  • Small-molecule NR4A1 agonists demonstrate proof-of-concept for anti-fibrotic therapy.

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