NF-κB-mediated EAAT3 upregulation in antioxidant defense and ferroptosis sensitivity in lung cancer
Abstract Cellular glutathione (GSH) in lung cancer cells represents the most abundant antioxidant. GSH production is regulated not only by upregulated cystine/glutamate exchanger (xCT) but also by the involvement of glutamate transporters, specifically excitatory amino acid transporter 3 (EAAT3). Ou...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07453-y |
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| author | Donghua Wen Wenjing Li Xiang Song Min Hu Yueling Liao Dongliang Xu Jiong Deng Wenzheng Guo |
| author_facet | Donghua Wen Wenjing Li Xiang Song Min Hu Yueling Liao Dongliang Xu Jiong Deng Wenzheng Guo |
| author_sort | Donghua Wen |
| collection | DOAJ |
| description | Abstract Cellular glutathione (GSH) in lung cancer cells represents the most abundant antioxidant. GSH production is regulated not only by upregulated cystine/glutamate exchanger (xCT) but also by the involvement of glutamate transporters, specifically excitatory amino acid transporter 3 (EAAT3). Our prior research established that the uptake of glutamate via EAAT3 plays a pivotal role in driving cystine uptake through xCT, contributing to GSH biosynthesis during lung tumorigenesis. Nevertheless, the underlying mechanism governing the upregulation of EAAT3 remains enigmatic. In this study, we conducted a comprehensive reanalysis of publicly available data and employed the Gprc5a–/–/SR-IκB mouse model alongside in vitro cell experiments to elucidate the correlations between NF-κB and EAAT3 in lung cancer. We observed that EAAT3 knockdown, similar to NF-κB inhibition, led to the accumulation of reactive oxygen species (ROS) and increased sensitivity to ferroptosis induction by RAS-selective lethal 3 (RSL3). Mechanistic insights were obtained through chromatin immunoprecipitation and luciferase reporter assays, revealing that NF-κB induces EAAT3 expression via two putative cis-elements within its promoter. Furthermore, our investigation unveiled the upregulation of EAAT3 in a subset of clinical non-small cell lung cancer (NSCLC) tissues, exhibiting a positive correlation with the P65 protein. In addition, the inflammatory factor of smoking was found to augment EAAT3 expression in both human and murine experimental models. These findings collectively emphasize the pivotal role of the NF-κB/EAAT3 axis in managing antioxidant stress and influencing lung cancer development. Moreover, this research offers insights into the potential for a combined ferroptosis therapy strategy in lung cancer treatment. |
| format | Article |
| id | doaj-art-e93289ca2bb4410c864db18e0a9e531f |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-e93289ca2bb4410c864db18e0a9e531f2025-08-20T03:04:53ZengNature Publishing GroupCell Death and Disease2041-48892025-02-0116111410.1038/s41419-025-07453-yNF-κB-mediated EAAT3 upregulation in antioxidant defense and ferroptosis sensitivity in lung cancerDonghua Wen0Wenjing Li1Xiang Song2Min Hu3Yueling Liao4Dongliang Xu5Jiong Deng6Wenzheng Guo7Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of MedicineDepartment of Laboratory Medicine, Shanghai East Hospital, Tongji University School of MedicineBreast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical SciencesDepartment of Laboratory Medicine, Shanghai East Hospital, Tongji University School of MedicineCollege of Life and Environmental Science, Wenzhou UniversityRenji Hospital, Shanghai Jiao Tong University School of MedicineMedical Research Center, Affiliated Hospital of Binzhou Medical UniversityDepartment of Laboratory Medicine, Shanghai East Hospital, Tongji University School of MedicineAbstract Cellular glutathione (GSH) in lung cancer cells represents the most abundant antioxidant. GSH production is regulated not only by upregulated cystine/glutamate exchanger (xCT) but also by the involvement of glutamate transporters, specifically excitatory amino acid transporter 3 (EAAT3). Our prior research established that the uptake of glutamate via EAAT3 plays a pivotal role in driving cystine uptake through xCT, contributing to GSH biosynthesis during lung tumorigenesis. Nevertheless, the underlying mechanism governing the upregulation of EAAT3 remains enigmatic. In this study, we conducted a comprehensive reanalysis of publicly available data and employed the Gprc5a–/–/SR-IκB mouse model alongside in vitro cell experiments to elucidate the correlations between NF-κB and EAAT3 in lung cancer. We observed that EAAT3 knockdown, similar to NF-κB inhibition, led to the accumulation of reactive oxygen species (ROS) and increased sensitivity to ferroptosis induction by RAS-selective lethal 3 (RSL3). Mechanistic insights were obtained through chromatin immunoprecipitation and luciferase reporter assays, revealing that NF-κB induces EAAT3 expression via two putative cis-elements within its promoter. Furthermore, our investigation unveiled the upregulation of EAAT3 in a subset of clinical non-small cell lung cancer (NSCLC) tissues, exhibiting a positive correlation with the P65 protein. In addition, the inflammatory factor of smoking was found to augment EAAT3 expression in both human and murine experimental models. These findings collectively emphasize the pivotal role of the NF-κB/EAAT3 axis in managing antioxidant stress and influencing lung cancer development. Moreover, this research offers insights into the potential for a combined ferroptosis therapy strategy in lung cancer treatment.https://doi.org/10.1038/s41419-025-07453-y |
| spellingShingle | Donghua Wen Wenjing Li Xiang Song Min Hu Yueling Liao Dongliang Xu Jiong Deng Wenzheng Guo NF-κB-mediated EAAT3 upregulation in antioxidant defense and ferroptosis sensitivity in lung cancer Cell Death and Disease |
| title | NF-κB-mediated EAAT3 upregulation in antioxidant defense and ferroptosis sensitivity in lung cancer |
| title_full | NF-κB-mediated EAAT3 upregulation in antioxidant defense and ferroptosis sensitivity in lung cancer |
| title_fullStr | NF-κB-mediated EAAT3 upregulation in antioxidant defense and ferroptosis sensitivity in lung cancer |
| title_full_unstemmed | NF-κB-mediated EAAT3 upregulation in antioxidant defense and ferroptosis sensitivity in lung cancer |
| title_short | NF-κB-mediated EAAT3 upregulation in antioxidant defense and ferroptosis sensitivity in lung cancer |
| title_sort | nf κb mediated eaat3 upregulation in antioxidant defense and ferroptosis sensitivity in lung cancer |
| url | https://doi.org/10.1038/s41419-025-07453-y |
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