Combining radiotherapy with Nrf-2 inhibitor holds promise as a potential therapeutic strategy for radioresistant lung cancer. Here, the radiosensitizing efficacy of a synthetic glucocorticoid clobetasol propionate (CP) in A549 human lung cancer cells was evaluated. CP exhibited potent radiosensitization in lung cancer cells via inhibition of Nrf-2 pathway, leading to elevation of oxidative stress. Transcriptomic studies revealed significant modulation of pathways related to ferroptosis, fatty acid and glutathione metabolism. Consistent with these findings, CP treatment followed by radiation exposure showed characteristic features of ferroptosis in terms of mitochondrial swelling, rupture and loss of cristae. Ferroptosis is a form of regulated cell death triggered by iron-dependent ROS accumulation and lipid peroxidation. In combination with radiation, CP showed enhanced iron release, mitochondrial ROS, and lipid peroxidation, indicating ferroptosis induction. Further, iron chelation, inhibition of lipid peroxidation or scavenging mitochondrial ROS prevented CP-mediated radiosensitization. Nrf-2 negatively regulates ferroptosis through upregulation of antioxidant defense and iron homeostasis. Interestingly, Nrf-2 overexpressing A549 cells were refractory to CP-mediated ferroptosis induction and radiosensitization. Thus, this study identified anti-psoriatic drug clobetasol propionate can be repurposed as a promising radiosensitizer for Keap-1 mutant lung cancers.

放射治疗与 Nrf-2 抑制剂相结合有望成为放射抗性肺癌的潜在治疗策略。在此，评估了合成糖皮质激素丙酸氯倍他索 (CP) 对 A549 人肺癌细胞的放射增敏功效。CP 通过抑制 Nrf-2 途径在肺癌细胞中表现出有效的放射增敏作用，导致氧化应激升高。转录组学研究揭示了与铁死亡、脂肪酸和谷胱甘肽代谢相关途径的显着调节。与这些发现一致的是，CP治疗后进行辐射暴露显示出铁死亡的特征，即线粒体肿胀、破裂和嵴丢失。铁死亡是一种由铁依赖性 ROS 积累和脂质过氧化引发的受调节细胞死亡形式。与辐射相结合，CP 显示出铁释放、线粒体 ROS 和脂质过氧化增强，表明铁死亡诱导。此外，铁螯合、抑制脂质过氧化或清除线粒体 ROS 可防止 CP 介导的放射增敏。Nrf-2 通过上调抗氧化防御和铁稳态来负向调节铁死亡。有趣的是，Nrf-2 过表达的 A549 细胞对 CP 介导的铁死亡诱导和放射增敏具有抵抗力。因此，这项研究发现抗银屑病药物丙酸氯倍他索可以重新用作 Keap-1 突变型肺癌的有前途的放射增敏剂。