ArticleCell death & disease2025
Orphan nuclear receptor 4A1 (NR4A1) and NR4A2 are endogenous regulators of CD71 and their ligands induce ferroptosis in breast cancer.
Article in Cell death & disease, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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
2 citing papers in PubMed.
- Cdk1-phosphorylated Nur77 accumulates at the centrosome during mitosis to regulate the Cep192-PLK1 signaling axis.Cell death & disease · 2026Article
- A Commentary on Dual Orphan Nuclear Receptor 4A1 (NR4A1) and NR4A2 Ligands.Journal of cellular immunology · 2026Article
Corrections and comments
- Update of
Authors and funding
11 authors.
Funding
Abstract
Ferroptosis is an iron-dependent cell death pathway that involves multiple genes, including the transferrin receptor (TFRC/CD71), glutathione peroxidase 4 (GPX4) and cystine-glutamate antiporter (SLC7A11). This study is based on the hypothesis that orphan nuclear receptor 4A1 (NR4A1) and NR4A2 maintain low levels of ferroptosis in triple negative breast cancer (TNBC) cells and bis-indole derived (CDIM) compounds act as NR4A1/2 ligands that induce ferroptosis by enhancing CD71 expression. 1,1-Bis(3'-indolyl)-1-(3,5-disubstitutedphenyl)methane (DIM-3,5) analogs were investigated for their cytotoxicity and effects on NR4A1 and NR4A2 regulated genes and induction of ferroptosis. Several assays also determined enhanced lipoperoxidation, reactive oxygen species and malondialdehyde formation in TNBC cells. Knockdown of NR4A1, NR4A2, Sp1 and Sp4 was carried out by RNA interference. Molecular mechanisms of NR4A1/2-mediated regulation of CD71 expression were determined using CD71-luciferase promoter constructs, overexpression of Sp1 and chromatin immunoprecipitation (ChIP) assays. Initial studies show that DIM-3,5 analogs act as an inverse NR4A1/NR4A2 agonists that downregulate the pro-oncogenic responses/gene products regulated by both receptors in TNBC cells. DIM-3,5 analogs also induced ROS, malondialdehyde and lipoperoxide formation in TNBC cells, and this was accompanied by decreased expression of GPX4 and SLC7A11 and induction of CD71. Induction of CD71, an important biomarker of ferroptosis was observed after treatment of TNBC cells with DIM-3,5 analogs, knockdown of NR4A1, NR4A2, Sp1 or Sp4 demonstrating that induction of CD71 was coregulated by both receptors. Moreover, both promoter and ChIP analysis indicated that NR4A1 and NR4A2 acted as ligand-dependent cofactors of Sp1/4-mediated expression of CD71 in TNBC cells. Thus, CD71, a key biomarker of ferroptosis is an NR4A1/2/Sp regulated gene that can be directly targeted by DIM-3,5 inverse NR4A1/2 agonists to induce ferroptosis in TNBC cells.
Indexed as
Identifiers
What OpenQuestion holds
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.