Ferroptosis has become a topic of rapidly growing interest in recent years, and has possible therapy implications in cancer therapy. Although excessive autophagy may contribute to ferroptosis, its underlying molecular mechanism remains largely unknown. Here, we provide novel evidence that the interplay between the signals of mechanistic target of rapamycin kinase (MTOR) and glutathione peroxidase 4 (GPX4) modulates autophagy-dependent ferroptosis in human pancreatic cancer cells. Both the classical autophagy inducer rapamycin and the classical ferroptosis activator RSL3 can block MTOR activation and cause GPX4 protein degradation in human pancreatic cancer cells. Moreover, GPX4 plays an essential role in the inhibition of autophagy-dependent ferroptosis induced by rapamycin and RSL3. Consequently, GPX4 depletion by RNAi enhances the anticancer activity of rapamycin and RSL3 in vitro or in vivo. These findings not only increase our understanding of stress responses in cell death, but may also raise the possibility of developing new antitumor therapy targeting autophagy-dependent cell death.

近年来，铁死亡已成为一个迅速增长的话题，并且在癌症治疗中可能具有治疗意义。尽管过度的自噬可能导致铁死亡，但其潜在的分子机制在很大程度上仍然未知。在这里，我们提供了新的证据，表明雷帕霉素激酶 (MTOR) 和谷胱甘肽过氧化物酶 4 (GPX4) 的机械靶标信号之间的相互作用调节人胰腺癌细胞中的自噬依赖性铁死亡。经典的自噬诱导剂雷帕霉素和经典的铁死亡激活剂 RSL3 都可以阻断 MTOR 激活并导致人胰腺癌细胞中的 GPX4 蛋白降解。此外，GPX4 在抑制雷帕霉素和 RSL3 诱导的自噬依赖性铁死亡中起重要作用。最后，RNAi 对 GPX4 的消耗增强了雷帕霉素和 RSL3 在体外或体内的抗癌活性。这些发现不仅增加了我们对细胞死亡应激反应的理解，而且还可能提高开发针对自噬依赖性细胞死亡的新抗肿瘤疗法的可能性。