ArticleScience advances2021
Genome-wide synthetic lethal screen unveils novel CAIX-NFS1/xCT axis as a targetable vulnerability in hypoxic solid tumors.
Article in Science advances, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
What it found
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Who cites it
65 citing papers in PubMed, 129 citations in OpenAlex.
- NFS1 activates PI3K/AKT/mTOR signaling to upregulate GPX4 expression and enhance ferroptosis resistance in osteosarcoma.Functional & integrative genomics · 2026Article
- Review
- Hypoxia-mediated chromatin accessibility reprogramming of CA9 induces treatment resistance in colorectal mucinous adenocarcinoma.Journal of gastroenterology · 2026Article
- Preclinical Theranostic Study ofACS omega · 2026Article
- Regulatory networks of iron sulfur cluster biology in cancer mechanisms and therapeutic perspectives.iScience · 2026Review
- Targeting ferroptosis in cancer: from mechanistic insights to therapeutic approaches.Molecular biomedicine · 2026Review
- Iron and metabolic rewiring in cancer.Oncogenesis · 2026Review
- Carbonic Anhydrase Inhibitors in Oncology.Sub-cellular biochemistry · 2026Review
- NFS1 Plays a Critical Role in Regulating Ferroptosis Homeostasis.Biomolecules · 2025Review
- Dual-function TA@CaCOJournal of nanobiotechnology · 2025Article
- Transforming cancer immunotherapy: integration of distinct immune-based approaches as redefined dual immunotherapy with potential third-sensitizer.Experimental hematology & oncology · 2025Review
- Targeting carbonic anhydrase IX/XII prevents the anti-ferroptotic effect of stromal lactic acid in prostate carcinoma.Molecular oncology · 2025Article
- A novel role for Neurog2 in MYCN driven neuroendocrine plasticity of prostate cancer.Oncogene · 2025Article
- Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality.Cell genomics · 2025Article
- Self-healable and pH-responsive spermidine/ferrous ion complexed hydrogel Co-loaded with CA inhibitor and glucose oxidase for combined cancer immunotherapy through triple ferroptosis mechanism.Bioactive materials · 2025Article
- Targeting Tumor-Associated Carbonic Anhydrases in Photothermal Therapy.ChemMedChem · 2025Review
- Identification of a Selective Inhibitor of Human NFS1, a Cysteine Desulfurase Involved in Fe-S Cluster Assembly, via Structure-Based Virtual Screening.International journal of molecular sciences · 2025Article
- NSUN2 lactylation drives cancer cell resistance to ferroptosis through enhancing GCLC-dependent glutathione synthesis.Redox biology · 2025Article
- Overexpression of the ferroptosis-related gene, NFS1, corresponds to gastric cancer growth and tumor immune infiltration.Open life sciences · 2025Article
- Regulatory role and therapeutic prospect of lactate modification in cancer.Frontiers in pharmacology · 2025Review
5 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
17 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The metabolic mechanisms involved in the survival of tumor cells within the hypoxic niche remain unclear. We carried out a synthetic lethal CRISPR screen to identify survival mechanisms governed by the tumor hypoxia-induced pH regulator carbonic anhydrase IX (CAIX). We identified a redox homeostasis network containing the iron-sulfur cluster enzyme, NFS1. Depletion of NFS1 or blocking cyst(e)ine availability by inhibiting xCT, while targeting CAIX, enhanced ferroptosis and significantly inhibited tumor growth. Suppression of CAIX activity acidified intracellular pH, increased cellular reactive oxygen species accumulation, and induced susceptibility to alterations in iron homeostasis. Mechanistically, inhibiting bicarbonate production by CAIX or sodium-driven bicarbonate transport, while targeting xCT, decreased adenosine 5'-monophosphate-activated protein kinase activation and increased acetyl-coenzyme A carboxylase 1 activation. Thus, an alkaline intracellular pH plays a critical role in suppressing ferroptosis, a finding that may lead to the development of innovative therapeutic strategies for solid tumors to overcome hypoxia- and acidosis-mediated tumor progression and therapeutic resistance.
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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 OpenQuestion graph.