Cuproptosis is characterized by the aggregation of lipoylated enzymes of the tricarboxylic acid cycle and subsequent loss of iron-sulfur cluster proteins as a unique copper-dependent form of regulated cell death. As dysregulation of copper homeostasis can induce cuproptosis, there is emerging interest in exploiting cuproptosis for cancer therapy. However, the molecular drivers of cancer cell evasion of cuproptosis were previously undefined. Here, we found that cuproptosis activates the Wnt/β-catenin pathway. Mechanistically, copper binds PDK1 and promotes its interaction with AKT, resulting in activation of the Wnt/β-catenin pathway and cancer stem cell (CSC) properties. Notably, aberrant activation of Wnt/β-catenin signaling conferred resistance of CSCs to cuproptosis. Further studies showed the β-catenin/TCF4 transcriptional complex directly binds the ATP7B promoter, inducing its expression. ATP7B effluxes copper ions, reducing intracellular copper and inhibiting cuproptosis. Knockdown of TCF4 or pharmacological Wnt/β-catenin blockade increased the sensitivity of CSCs to elesclomol-Cu-induced cuproptosis. These findings reveal a link between copper homeostasis regulated by the Wnt/β-catenin pathway and cuproptosis sensitivity, and suggest a precision medicine strategy for cancer treatment through selective cuproptosis induction.

铜中毒的特征是三羧酸循环的硫辛酸化酶的聚集以及随后铁硫簇蛋白的丢失，这是一种独特的铜依赖性调节细胞死亡形式。由于铜稳态失调可诱发铜凋亡，因此人们对利用铜凋亡进行癌症治疗产生了兴趣。然而，癌细胞逃避铜凋亡的分子驱动因素此前尚不清楚。在这里，我们发现铜凋亡激活 Wnt/β-catenin 通路。从机制上讲，铜结合 PDK1 并促进其与 AKT 相互作用，从而激活 Wnt/β-catenin 通路和癌症干细胞 (CSC) 特性。值得注意的是，Wnt/β-catenin 信号传导的异常激活赋予 CSC 对铜凋亡的抵抗力。进一步的研究表明，β-catenin/TCF4 转录复合物直接结合 ATP7B 启动子，诱导其表达。 ATP7B 流出铜离子，减少细胞内铜并抑制铜凋亡。 TCF4 的敲低或药理学 Wnt/β-连环蛋白阻断增加了 CSC 对艾司氯醇-铜诱导的铜凋亡的敏感性。这些发现揭示了 Wnt/β-catenin 通路调节的铜稳态与铜凋亡敏感性之间的联系，并提出了通过选择性铜凋亡诱导来治疗癌症的精准医学策略。