ArticleCancer discovery2024
BRCA1-Mediated Dual Regulation of Ferroptosis Exposes a Vulnerability to GPX4 and PARP Co-Inhibition in BRCA1-Deficient Cancers.
Article in Cancer discovery, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 44 citations in OpenAlex.
- Research progress of ferroptosis in gynecological diseases.Annals of medicine · 2026Review
- METTL14-Mediated N6-Methyladenosine Exacerbates Acute Lung Injury via USP30/NCOA4-Dependent Ferroptosis.MedComm · 2026Article
- Size-Dependent Differences in the Effects of Low-Dose Selenium Nanoparticles on Chronic Thioacetamide Toxicosis Accompanying HCC Progression in Mice.Biological trace element research · 2026Article
- DHODH-Mediated Suppression of Ferroptosis Supports Radioresistance and Represents a Therapeutic Vulnerability in Lung Cancer.Cancer research · 2026Article
- Divergent roles of SPOP and CHD1 in ACSL4 regulation reveal context-dependent vulnerabilities for targeting ferroptosis.Nature communications · 2026Article
- Translating ferroptosis into oncology: challenges, opportunities and future directions.Nature reviews. Clinical oncology · 2026Review
- Multiplexed Transcriptomics for Screening Drug Combinations and Defining the Mechanism of Action of HCC Therapeutics at Single-Cell Resolution.Cell proliferation · 2026Article
- Finding novel vulnerabilities of hypomorphic BRCA1 alleles.Molecular oncology · 2026Article
- KMT2C Loss Promotes NF2-Wildtype Meningioma Progression and Ferroptosis Sensitivity via Epigenetic Repression of Hippo Signaling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- IFI16 is essential to linking DNA damage and ferroptosis in acute kidney injury.Cell death & disease · 2026Article
- Repurposing dronedarone induces ferroptosis through GPX4 inactivation and degradation in pancreatic cancer.Journal of experimental & clinical cancer research : CR · 2026Article
- The Role of Se-Containing Glutathione Peroxidases and Thioredoxin Reductases in Oncogenesis: Expression Paradoxes and Therapeutic Prospects.Antioxidants (Basel, Switzerland) · 2026Review
- Targeting de novo pyrimidine synthesis confers vulnerability to copper-mediated ATR inactivation in PARP inhibitor-resistant ovarian cancer.Nature communications · 2026Article
- Ferroptosis: A Double-Edged Sword in Cisplatin-Based Cancer Therapy and Acute Kidney Injury.Cancer management and research · 2026Review
- Exploiting metabolic cell death for cancer therapy.Nature reviews. Cancer · 2026Review
- Exploring Lipid Metabolic Reprogramming: Mechanistic Insights and Implications for Tumor Radiotherapy.International journal of biological sciences · 2026Review
- CCNE1 Exerts a Protective Effect on Parkinson's Disease by Regulating Ferroptosis-Related Proteins.Brain and behavior · 2025Article
- Co-targeting ferroptosis and immune evasion through small molecules in breast cancer.Journal of translational internal medicine · 2025Article
- IRG1/itaconate/NRF2/GSH axis in tumor-associated macrophages drives therapy resistance and immune evasion in BRCA1-deficient breast cancer.bioRxiv : the preprint server for biology · 2025Article
- Chlorogenic acid mitigates ferroptosis in macrophages induced by pneumolysin and streptococcus pneumoniae through activation of NRF2/GPX4 pathway.BMC immunology · 2025Article
Corrections and comments
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Authors and funding
22 authors at 1 institution in 1 country.
Funding
Abstract
Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) limits the therapeutic efficacy of PARP inhibition in treating breast cancer susceptibility gene 1 (BRCA1)-deficient cancers. Here we reveal that BRCA1 has a dual role in regulating ferroptosis. BRCA1 promotes the transcription of voltage-dependent anion channel 3 (VDAC3) and glutathione peroxidase 4 (GPX4); consequently, BRCA1 deficiency promotes cellular resistance to erastin-induced ferroptosis but sensitizes cancer cells to ferroptosis induced by GPX4 inhibitors (GPX4i). In addition, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and defective GPX4 induction unleash potent ferroptosis in BRCA1-deficient cancer cells upon PARPi and GPX4i co-treatment. Finally, we show that xenograft tumors derived from patients with BRCA1-mutant breast cancer with PARPi resistance exhibit decreased GPX4 expression and high sensitivity to PARP and GPX4 co-inhibition. Our results show that BRCA1 deficiency induces a ferroptosis vulnerability to PARP and GPX4 co-inhibition and inform a therapeutic strategy for overcoming PARPi resistance in BRCA1-deficient cancers. Significance: BRCA1 deficiency promotes resistance to erastin-induced ferroptosis via blocking VDAC3 yet renders cancer cells vulnerable to GPX4i-induced ferroptosis via inhibiting GPX4. NCOA4 induction and defective GPX4 further synergizes GPX4i with PARPi to induce ferroptosis in BRCA1-deficient cancers and targeting GPX4 mitigates PARPi resistance in those cancers. See related commentary by Alborzinia and Friedmann Angeli, p. 1372.
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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 Socratic graph.