Resistance to cisplatin (DDP)-based chemotherapy is an important reason for the failure of ovarian cancer treatment. However, tumor cells resistant to chemotherapy may expose vulnerability to other cell death pathways. Here, we found that DDP-resistant ovarian cancer cells are more susceptible to erastin-induced ferroptosis. It should be noted that this vulnerability does not depend on the weakening of classical ferroptosis defense proteins, but is caused by the reduction of ferritin heavy chain (FTH1). DDP-resistant ovarian cancer cells maintain a high level of autophagy to escape the pressure of chemotherapy, which ultimately leads to increased autophagic degradation of FTH1. We further revealed that the loss of AKT1 was the reason for the increased autophagy level of DDP-resistant ovarian cancer cells. Our study provides new insights into reversing DDP resistance in ovarian cancer by targeting ferroptosis pathway, and AKT1 may be a molecular marker of susceptibility to ferroptosis.

中文翻译：

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AKT1 通过驱动顺铂耐药卵巢癌中 FTH1 的自噬降解参与铁死亡脆弱性。

对顺铂（DDP）化疗耐药是卵巢癌治疗失败的重要原因。然而，对化疗有抵抗力的肿瘤细胞可能容易受到其他细胞死亡途径的影响。在这里，我们发现 DDP 抗性卵巢癌细胞更容易受到erastin诱导的铁死亡的影响。需要注意的是，这种脆弱性并不依赖于经典铁死亡防御蛋白的减弱，而是由铁蛋白重链（FTH1）的减少引起的。DDP耐药的卵巢癌细胞为了逃避化疗的压力而维持高水平的自噬，最终导致FTH1的自噬降解增加。我们进一步发现AKT1的缺失是DDP耐药性卵巢癌细胞自噬水平升高的原因。我们的研究为通过靶向铁死亡途径逆转卵巢癌中的 DDP 耐药性提供了新的见解，AKT1 可能是铁死亡易感性的分子标志物。