为了提高放射治疗（RT）对人乳头瘤病毒（HPV）阴性头颈鳞状细胞癌（HNSCC）的疗效，我们探索了针对铁死亡（一种受调节的细胞死亡过程）的靶向治疗。我们在接受 RT 的 HPV 阴性 HNSCC 患者中使用 Cox 比例风险模型开发了与铁死亡相关的基因特征。这种铁死亡相关基因特征 (FRGS) 是接受 RT 的 HPV 阴性 HNSCC 患者总生存期和无复发生存期的重要预测因子。 FRGS 的 B 亚型，其特征是铁死亡诱​​导剂 [核受体辅激活剂 4 (NCOA4) 和天然抗性相关巨噬细胞蛋白 2 同源物/二价金属转运蛋白 1 (NRAMP2/DMT1)] 的表达减少，以及抑制剂 [磷脂过氧化氢谷胱甘肽] 的表达增加过氧化物酶（GPX4）和铁蛋白重链（FTH1）]与较差的预后相关，可能表明铁死亡的抑制。此外，我们的体外和体内研究表明，他汀类药物（如阿托伐他汀和辛伐他汀）治疗可诱导铁死亡并使抗辐射的 HNSCC 细胞对辐射敏感，提高放射敏感性并可能增强对放疗的反应。此外，在异种移植模型中，他汀类药物和放疗的组合可显着减少肿瘤的发生。这些发现为通过靶向铁死亡和利用他汀类药物使肿瘤对 RT 诱导的细胞死亡敏感来加强 HPV 阴性 HNSCC 的治疗和改善预后提供了宝贵的见解。© 2024 作者。约翰·威利出版的《分子肿瘤学》

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.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.