Targeting ferroptosis for improved radiotherapy outcomes in HPV‐negative head and neck squamous cell carcinoma
To enhance the efficacy of radiotherapy (RT) in human papillomavirus (HPV)‐negative head and neck squamous cell carcinoma (HNSCC), we explored targeting ferroptosis, a regulated cell death process. We developed a gene signature associated with ferroptosis using Cox proportional hazard modeling in HP...
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| Format: | Article |
| Language: | English |
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Wiley
2025-02-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.13720 |
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| author | Joo Kyung Noh Min Kyeong Lee Yeonseo Lee Minji Bae Soonki Min Moonkyoo Kong Jung Woo Lee Su Il Kim Young Chan Lee Seong‐Gyu Ko Seon Rang Woo Young‐Gyu Eun |
| author_facet | Joo Kyung Noh Min Kyeong Lee Yeonseo Lee Minji Bae Soonki Min Moonkyoo Kong Jung Woo Lee Su Il Kim Young Chan Lee Seong‐Gyu Ko Seon Rang Woo Young‐Gyu Eun |
| author_sort | Joo Kyung Noh |
| collection | DOAJ |
| description | To enhance the efficacy of radiotherapy (RT) in human papillomavirus (HPV)‐negative head and neck squamous cell carcinoma (HNSCC), we explored targeting ferroptosis, a regulated cell death process. We developed a gene signature associated with ferroptosis using Cox proportional hazard modeling in HPV‐negative HNSCC patients who underwent RT. This ferroptosis‐related gene signature (FRGS) was a significant predictor of overall survival and recurrence‐free survival in HPV‐negative HNSCC patients who received RT. Subtype B of the FRGS, characterized by decreased expression of ferroptosis inducers [nuclear receptor coactivator 4 (NCOA4) and natural resistance‐associated macrophage protein 2 homolog/divalent metal transporter 1 (NRAMP2/DMT1)] and increased expression of suppressors [phospholipid hydroperoxide glutathione peroxidase (GPX4) and ferritin heavy chain (FTH1)], was associated with poorer prognosis, potentially indicating the inhibition of ferroptosis. Furthermore, our in vitro and in vivo studies demonstrated that treatment with statins, such as atorvastatin and simvastatin, induced ferroptosis and sensitized radioresistant HNSCC cells to irradiation, improving radiosensitivity and potentially enhancing the response to RT. Additionally, in xenograft models, the combination of statins and RT led to a significant reduction in tumor initiation. These findings provide valuable insights for enhancing treatment and improving prognosis in HPV‐negative HNSCC by targeting ferroptosis and utilizing statins to sensitize tumors to RT‐induced cell death. |
| format | Article |
| id | doaj-art-73dfa3fef39c4ff0afd8e5200d3101ae |
| institution | Kabale University |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-73dfa3fef39c4ff0afd8e5200d3101ae2025-02-04T17:30:20ZengWileyMolecular Oncology1574-78911878-02612025-02-0119254055710.1002/1878-0261.13720Targeting ferroptosis for improved radiotherapy outcomes in HPV‐negative head and neck squamous cell carcinomaJoo Kyung Noh0Min Kyeong Lee1Yeonseo Lee2Minji Bae3Soonki Min4Moonkyoo Kong5Jung Woo Lee6Su Il Kim7Young Chan Lee8Seong‐Gyu Ko9Seon Rang Woo10Young‐Gyu Eun11Department of Biomedical Science and Technology, Graduate School Kyung Hee University Seoul KoreaDepartment of Biomedical Science and Technology, Graduate School Kyung Hee University Seoul KoreaDepartment of Biomedical Science and Technology, Graduate School Kyung Hee University Seoul KoreaDepartment of Biomedical Science and Technology, Graduate School Kyung Hee University Seoul KoreaDepartment of Radiation Oncology Kyung Hee University School of Medicine, Kyung Hee University Medical Center Seoul KoreaDepartment of Radiation Oncology Kyung Hee University School of Medicine, Kyung Hee University Medical Center Seoul KoreaDepartment of Oral and Maxillofacial Surgery, School of Dentistry Kyung Hee University Seoul KoreaDepartment of Otolaryngology‐Head and Neck Surgery Kyung Hee University School of Medicine, Kyung Hee University Medical Center Seoul KoreaDepartment of Otolaryngology‐Head and Neck Surgery Kyung Hee University School of Medicine, Kyung Hee University Medical Center Seoul KoreaDepartment of Preventive Medicine, College of Korean Medicine Kyung Hee University Seoul KoreaDepartment of Otolaryngology‐Head and Neck Surgery Kyung Hee University School of Medicine, Kyung Hee University Medical Center Seoul KoreaDepartment of Biomedical Science and Technology, Graduate School Kyung Hee University Seoul KoreaTo enhance the efficacy of radiotherapy (RT) in human papillomavirus (HPV)‐negative head and neck squamous cell carcinoma (HNSCC), we explored targeting ferroptosis, a regulated cell death process. We developed a gene signature associated with ferroptosis using Cox proportional hazard modeling in HPV‐negative HNSCC patients who underwent RT. This ferroptosis‐related gene signature (FRGS) was a significant predictor of overall survival and recurrence‐free survival in HPV‐negative HNSCC patients who received RT. Subtype B of the FRGS, characterized by decreased expression of ferroptosis inducers [nuclear receptor coactivator 4 (NCOA4) and natural resistance‐associated macrophage protein 2 homolog/divalent metal transporter 1 (NRAMP2/DMT1)] and increased expression of suppressors [phospholipid hydroperoxide glutathione peroxidase (GPX4) and ferritin heavy chain (FTH1)], was associated with poorer prognosis, potentially indicating the inhibition of ferroptosis. Furthermore, our in vitro and in vivo studies demonstrated that treatment with statins, such as atorvastatin and simvastatin, induced ferroptosis and sensitized radioresistant HNSCC cells to irradiation, improving radiosensitivity and potentially enhancing the response to RT. Additionally, in xenograft models, the combination of statins and RT led to a significant reduction in tumor initiation. These findings provide valuable insights for enhancing treatment and improving prognosis in HPV‐negative HNSCC by targeting ferroptosis and utilizing statins to sensitize tumors to RT‐induced cell death.https://doi.org/10.1002/1878-0261.13720ferroptosisgene signaturehead and neck squamous cell carcinomaradiation therapystatin |
| spellingShingle | Joo Kyung Noh Min Kyeong Lee Yeonseo Lee Minji Bae Soonki Min Moonkyoo Kong Jung Woo Lee Su Il Kim Young Chan Lee Seong‐Gyu Ko Seon Rang Woo Young‐Gyu Eun Targeting ferroptosis for improved radiotherapy outcomes in HPV‐negative head and neck squamous cell carcinoma Molecular Oncology ferroptosis gene signature head and neck squamous cell carcinoma radiation therapy statin |
| title | Targeting ferroptosis for improved radiotherapy outcomes in HPV‐negative head and neck squamous cell carcinoma |
| title_full | Targeting ferroptosis for improved radiotherapy outcomes in HPV‐negative head and neck squamous cell carcinoma |
| title_fullStr | Targeting ferroptosis for improved radiotherapy outcomes in HPV‐negative head and neck squamous cell carcinoma |
| title_full_unstemmed | Targeting ferroptosis for improved radiotherapy outcomes in HPV‐negative head and neck squamous cell carcinoma |
| title_short | Targeting ferroptosis for improved radiotherapy outcomes in HPV‐negative head and neck squamous cell carcinoma |
| title_sort | targeting ferroptosis for improved radiotherapy outcomes in hpv negative head and neck squamous cell carcinoma |
| topic | ferroptosis gene signature head and neck squamous cell carcinoma radiation therapy statin |
| url | https://doi.org/10.1002/1878-0261.13720 |
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