ArticleClinical and translational medicine2021
Glutathione peroxidase 4-dependent glutathione high-consumption drives acquired platinum chemoresistance in lung cancer-derived brain metastasis.
Article in Clinical and translational medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 96 citations in OpenAlex.
- Carrier-Free Berberine/Nitidine Chloride Self-Assembled Nanoparticles Induce Ferroptosis to Overcome Bortezomib Resistance in Multiple Myeloma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- A Non-Canonical Core Transcriptional Regulatory Circuit Orchestrates Chromatin Reprogramming to Drive Osimertinib Resistance in Non-Small Cell Lung Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- GSH-Related Enzymes GPx4, Chac1, and GSTs and Redox Regulation of Ferroptosis in Cancer.International journal of molecular sciences · 2026Review
- Review
- Targeting shared mechanisms of cisplatin resistance and metastasis in lung cancer for novel therapeutic strategies.Discover oncology · 2026Review
- GPX4 Inhibition Enhances the Antitumor Effect of PARP Inhibitor on Homologous Recombination Proficient Ovarian Cancer Cells.Current cancer drug targets · 2026Article
- Targeting glutathione peroxidase 4 in ferroptosis: from immune regulation to pharmacological development and translational applications.Frontiers in pharmacology · 2026Review
- CD146Theranostics · 2026Article
- From Fibrosis to Malignancy: Mechanistic Intersections Driving Lung Cancer Progression.Cancers · 2025Review
- [Expression Characteristics and Prognostic Study of PPP1R13L in Brain Metastases of Lung Adenocarcinoma].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2025Article
- Inhibition of NR2F2 suppresses invasion ability and modulates EMT marker in head and neck squamous cell carcinoma.Discover oncology · 2025Article
- SLC25A39 overexpression exacerbates lung adenocarcinoma progression and is negatively regulated by AFG3L2.NPJ precision oncology · 2025Article
- Metabolic adaptations of brain metastasis.Nature reviews. Cancer · 2025Review
- Clinical Features, Molecular Biology, and the Metastatic Microenvironment in Lung Cancer Brain Metastases: Implications for Treatment Decisions.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Intersection of ferroptosis and nanomaterials brings benefits to breast cancer.Cell biology and toxicology · 2025Review
- [Applications and Advances of Metabolomics in Lung Cancer Research].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2025Review
- GSTM1 suppresses cardiac fibrosis post-myocardial infarction through inhibiting lipid peroxidation and ferroptosis.Military Medical Research · 2025Article
- ELANE enhances KEAP1 protein stability and reduces NRF2-mediated ferroptosis inhibition in metabolic dysfunction-associated fatty liver disease.Cell death & disease · 2025Article
- Ferroptosis-related signaling pathways in cancer drug resistance.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Integrative single-cell RNA sequencing and bulk RNA sequencing reveals the characteristics of glutathione metabolism and protective role of GSTA4 gene in pancreatic cancer.Frontiers in immunology · 2025Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundPlatinum-based chemotherapy is effective in inducing shrinkage of primary lung cancer lesions; however, it shows finite therapeutic efficacy in patients suffering from brain metastasis (BM). The intrinsic changes of BM cells, which contribute to the poor results remain unknown.
methodsPlatinum drug-sensitivity was assessed by utilizing a preclinical BM model of PC9 lung adenocarcinoma cells in vitro and in vivo. High consumption of glutathione (GSH) and two associated upregulated proteins (GPX4 and GSTM1) in BM were identified by integrated metabolomics and proteomics in cell lines and verified by clinical serum sample. Gain-of-function and rescue experiments were implemented to reveal the impact and mechanism of GPX4 and GSTM1 on the chemosensitivity in BM. The interaction between GPX4 and GSTM1 was examined by immunoblotting and immunoprecipitation. The mechanism of upregulation of GPX4 was further uncovered by luciferase reporter assay, immunoprecipitation, and electrophoretic mobility shift assay.
resultsThe derivative brain metastatic subpopulations (PC9-BrMs) of parental cells PC9 developed obvious resistance to platinum. Radically altered profiles of BM metabolism and protein expression compared with primary lung cancer cells were described and GPX4 and GSTM1 were identified as being responsible for the high consumption of GSH, leading to decreased chemosensitivity by negatively regulating ferroptosis. Besides, GSTM1 was found regulated by GPX4, which was transcriptionally activated by the Wnt/NR2F2 signaling axis in BM.
conclusionsCollectively, our findings demonstrated that Wnt/NR2F2/GPX4 promoted acquired chemoresistance by suppressing ferroptosis with high consumption of GSH. GPX4 inhibitor was found to augment the anticancer effect of platinum drugs in lung cancer BM, providing novel strategies for lung cancer patients with BM.
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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.