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Commentary Open Access
Volume 8 | Issue 1 | DOI: https://doi.org/10.33696/immunology.8.251

A Commentary on Dual Orphan Nuclear Receptor 4A1 (NR4A1) and NR4A2 Ligands

  • 1Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA
  • 2Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA
  • 3Department of Nutrition, Texas A&M University, College Station, TX 77843, USA
  • 4Single Cell Data Science Core, Texas A&M Regional Center of Excellence in Cancer, College Station, TX 77843, USA
+ Affiliations - Affiliations

Corresponding Author

Stephen Safe, ssafe@cvm.tamu.edu

Received Date: March 05, 2026

Accepted Date: April 21, 2026

Abstract

1,1-Bis(3’-indolyl)-1-(3,5-disubstitutedphenyl)methane (DIM-3,5) compounds in the presence or absence of a 4-hydroxylphenyl group bind both orphan nuclear receptor 4A1 (NR4A1) and NR4A2. In cancer cells, these compounds bind and inactivate pro-oncogenic NR4A1 and NR4A2 and downstream pathways acting as inverse agonists that inhibit cancer cell growth, survival, migration and invasion, and induce ferroptosis. Similar results are observed in endometriotic cells where the DIM-3,5 dual NR4A1/2 ligands inhibit NR4A1/NR4A2-mediated pro-endometriotic genes and pathways. The potency of these DIM-3,5 dual NR4A1/NR4A2 ligands is also observed in tumor infiltrating lymphocytes where both receptors are expressed and regulate comparable functions.

Keywords

NR4A1, NR4A2, Dual receptor ligands, Inverse agonists, Cancer, Endometriosis, T cell exhaustion

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