三氧化二砷（ATO）在治疗急性早幼粒细胞白血病（APL）方面表现出显着的疗效，主要是通过促进 PML-RARα 融合蛋白的降解。然而，单独使用 ATO 无法为非 APL 急性髓系白血病 (AML) 患者带来任何生存获益，并且与其他药物联合使用时疗效有限。在这里，我们探讨了 ATO 在 APL 中的一般毒性机制，以及可以与 ATO 组合对其他 AML 表现出协同致死作用的潜在药物。我们证明 PML-RARα 降解和 ROS 上调不足以导致 APL 细胞死亡。基于不同AML细胞的蛋白质合成及其对ATO的敏感性，我们建立了ATO诱导的细胞死亡与蛋白质合成之间的相关性。我们的研究结果表明，ATO 通过破坏新生多肽并导致核糖体停滞来诱导细胞死亡，同时激活 ZAKα-JNK 通路。此外，ATO 诱导的应激激活了 GCN2-ATF4 通路，核糖体相关的质量控制在 p97 的帮助下清除了受损的蛋白质。重要的是，我们的数据表明，抑制 p97 增强了 ATO 杀死 AML 细胞的有效性。这些探索为确定最佳合成致死药物以增强 ATO 对非 APL AML 的治疗铺平了道路。© 2024。作者。

Arsenic trioxide (ATO) has exhibited remarkable efficacy in treating acute promyelocytic leukemia (APL), primarily through promoting the degradation of the PML-RARα fusion protein. However, ATO alone fails to confer any survival benefit to non-APL acute myeloid leukemia (AML) patients and exhibits limited efficacy when used in combination with other agents. Here, we explored the general toxicity mechanisms of ATO in APL and potential drugs that could be combined with ATO to exhibit synergistic lethal effects on other AML. We demonstrated that PML-RARα degradation and ROS upregulation were insufficient to cause APL cell death. Based on the protein synthesis of different AML cells and their sensitivity to ATO, we established a correlation between ATO-induced cell death and protein synthesis. Our findings indicated that ATO induced cell death by damaging nascent polypeptides and causing ribosome stalling, accompanied by the activation of the ZAKα-JNK pathway. Furthermore, ATO-induced stress activated the GCN2-ATF4 pathway, and ribosome-associated quality control cleared damaged proteins with the assistance of p97. Importantly, our data revealed that inhibiting p97 enhanced the effectiveness of ATO in killing AML cells. These explorations paved the way for identifying optimal synthetic lethal drugs to enhance ATO treatment on non-APL AML.© 2024. The Author(s).