Radiotherapy is a common therapy method for nasopharyngeal carcinoma (NPC) treatment; however, radioresistance greatly limits the clinical efficiency and prognosis of NPC patients. Therefore, it is extremely urgent to reveal the underlying mechanism contributing to radioresistance and find possible diagnostic biomarkers. Here, we collected the spheroids formed by NPC cells, which had been confirmed to hold the stem cell‐like traits, and found that these spheroids exhibited a certain degree of radioresistance. Additionally, NPC spheroids displayed a certain degree of ferroptosis resistance, as evident by the decrease of iron concentration in lysosomes and lipid peroxides oxygen, and increase of glutathione (GSH) level. Furthermore, we revealed that itraconazole triggered the ferroptosis of NPC spheroids, which is characterized as the increase of iron concentration and lipid peroxides oxygen, and decrease of GSH level, and decreased the cell viability of NPC spheroids. Notably, itraconazole partially reversed the radioresistance of NPC spheroids. Mechanistically, we found that itraconazole can sequester iron in lysosome and thus trigger ferroptosis; this is essential for itraconazole‐mediated attenuation on NPC spheroid stemness. Therefore, this study provides evidences showing that itraconazole might be used for killing NPC stem cells and thus attenuate radioresistance.

中文翻译：

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伊曲康唑通过触发铁死亡减弱鼻咽癌细胞的干性

放射治疗是鼻咽癌（NPC）治疗的常用治疗方法；然而，放射抗性极大地限制了鼻咽癌患者的临床效率和预后。因此，揭示导致放射抗性的潜在机制并寻找可能的诊断生物标志物迫在眉睫。在这里，我们收集了由 NPC 细胞形成的球体，这些球体已被证实具有干细胞样特征，并发现这些球体表现出一定程度的辐射抗性。此外，NPC 球体显示出一定程度的抗铁死亡，这可以通过溶酶体中铁浓度和脂质过氧化物氧浓度的降低以及谷胱甘肽 (GSH) 水平的增加来证明。此外，我们发现伊曲康唑引发了 NPC 球体的铁死亡，其特点是铁浓度和脂质过氧化物氧含量增加，谷胱甘肽水平降低，降低了NPC球体的细胞活力。值得注意的是，伊曲康唑部分逆转了 NPC 球体的抗辐射性。从机制上讲，我们发现伊曲康唑可以螯合溶酶体中的铁，从而引发铁死亡；这对于伊曲康唑介导的 NPC 球体干性衰减至关重要。因此，本研究提供了证据表明伊曲康唑可能用于杀死鼻咽癌干细胞，从而减弱放射抗性。我们发现伊曲康唑可以螯合溶酶体中的铁，从而引发铁死亡；这对于伊曲康唑介导的 NPC 球体干性衰减至关重要。因此，本研究提供了证据表明伊曲康唑可能用于杀死鼻咽癌干细胞，从而减弱放射抗性。我们发现伊曲康唑可以螯合溶酶体中的铁，从而引发铁死亡；这对于伊曲康唑介导的 NPC 球体干性衰减至关重要。因此，本研究提供了证据表明伊曲康唑可能用于杀死鼻咽癌干细胞，从而减弱放射抗性。