虽然铁死亡在抗癌策略中显示出前景，但这一过程背后的分子机制仍然知之甚少。我们的研究旨在强调通过 NRF2/PHKG2 轴介导的机制对非小细胞肺癌 (NSCLC) 中放疗诱导的铁死亡的调节。为了鉴定与 NSCLC 放射抗性相关的铁死亡相关基因，本研究采用了高通量转录组测序和 Lasso 风险回归分析。分析临床样本以确认放疗前后 PHKG2 表达的变化。该研究进一步检测了接受辐射暴露的NSCLC细胞中的铁蛋白自噬相关因子、细胞内铁水平、线粒体功能和铁死亡，以探讨PHKG2对放射敏感性或放射抗性的影响。该研究还证明了NRF2对PHKG2的转录抑制作用，并建立了NSCLC原位移植肿瘤模型，以考察NRF2/PHKG2轴在NSCLC体内放射敏感性和耐药性中的作用。纳入铁死亡相关基因的Lasso风险回归模型有效预测了NSCLC患者的预后。放射治疗敏感组织中 PHKG2 的表达增加。 PHKG2 的过度表达通过促进铁蛋白自噬而导致细胞内铁水平升高，并增加放疗诱导的线粒体应激依赖性铁死亡。 PHKG2 转录抑制是通过 NRF2 实现的。 FAGs-Lasso风险回归模型可以准确预测NSCLC患者的预后。靶向 Nrf2 上调 PHKG2 的表达，通过促进铁自噬和诱导线粒体功能障碍逆转 NSCLC 的放疗抵抗，从而提高放疗敏感性。© 2024。作者。

While ferroptosis shows promise in anti-cancer strategy, the molecular mechanisms behind this process remain poorly understood. Our research aims to highlight the regulation of radiotherapy-induced ferroptosis in non-small cell lung cancer (NSCLC) via the NRF2/PHKG2 axis-mediated mechanism. To identify ferroptosis-associated genes associated with radioresistance in NSCLC, this study employed high-throughput transcriptome sequencing and Lasso risk regression analysis. Clinical samples were analyzed to confirm PHKG2 expression changes before and after radiotherapy. The study further examined ferritinophagy-related factors, intracellular iron levels, mitochondrial function, and ferroptosis in NSCLC cells undergoing radiation exposure to explore the effect of PHKG2 on radiosensitivity or radioresistance. The research also demonstrated the transcriptional inhibition of PHKG2 by NRF2 and created in situ transplantation tumor models of NSCLC to examine the role of NRF2/PHKG2 axis in NSCLC radiosensitivity and resistance in vivo. The Lasso risk regression model that incorporated ferroptosis-associated genes effectively predicted the prognosis of patients with NSCLC. Radiotherapy-sensitive tissues exhibited an increased expression of PHKG2. Overexpression of PHKG2 led to elevated intracellular iron levels by promoting ferritinophagy and increased mitochondrial stress-dependent ferroptosis induced by radiotherapy. PHKG2 transcription repression was achieved through NRF2. The FAGs-Lasso risk regression model can accurately predict the prognosis of NSCLC patients. Targeting Nrf2 upregulates the expression of PHKG2 and reverses radiotherapy resistance in NSCLC by promoting iron autophagy and inducing mitochondrial dysfunction, thereby increasing radiotherapy sensitivity.© 2024. The Author(s).