铜超载引起的铜中毒是由一种新的调节机制介导的，该机制不同于以前记录的调节细胞死亡的机制。依赖线粒体呼吸的细胞对诱导铜凋亡的铜离子载体艾司氯醇的敏感性增加。母体胚胎亮氨酸拉链激酶（MELK）通过PI3K/mTOR通路促进肿瘤发生和进展，部分通过靶向丙酮酸脱氢酶复合物（PDHc）并重编程线粒体的形态和功能来发挥作用。然而，MELK 在铜凋亡中的作用仍不清楚。在这里，我们验证了 MELK 表达升高增强了 PI3K/mTOR 信号传导的活性，随后促进二氢硫辛酰胺 S-乙酰转移酶 (DLAT) 表达并稳定线粒体功能。这种调节作用有助于改善线粒体呼吸，消除细胞内过多的活性氧（ROS），减少细胞内氧化应激/损伤以及线粒体诱导细胞命运改变的可能性，最终促进HCC的进展。同时，艾司洛醇减少了线粒体外膜转位酶 20 (TOM 20) 的表达并增加了 DLAT 寡聚物。而且，Esclomol消除了MELK对HCC的上述变化。总之，MELK通过激活PI3K/mTOR通路，提高铜凋亡相关特征（CRS）基因DLAT的水平（特别是DLAT单体的比例），从而促进艾司洛莫耐药，改变线粒体功能，最终促进HCC进展。 © 2023。作者。

Cuproptosis caused by copper overload is mediated by a novel regulatory mechanism that differs from previously documented mechanisms regulating cell death. Cells dependent on mitochondrial respiration showed increased sensitivity to a copper ionophore elesclomol that induced cuproptosis. Maternal embryonic leucine zipper kinase(MELK) promotes tumorigenesis and tumor progression through the PI3K/mTOR pathway, which exerts its effects partly by targeting the pyruvate dehydrogenase complex(PDHc) and reprogramming the morphology and function of mitochondria. However, the role of MELK in cuproptosis remains unclear. Here, we validated that elevated MELK expression enhanced the activity of PI3K/mTOR signaling and subsequently promoted Dihydrolipoamide S-Acetyltransferase (DLAT) expression and stabilized mitochondrial function. This regulatory effect helped to improve mitochondrial respiration, eliminate excessive intracellular reactive oxygen species (ROS), reduce intracellular oxidative stress/damage and the possibility of mitochondria-induced cell fate alternations, and ultimately promote the progression of HCC. Meanwhile, elesclomol reduced translocase of outer mitochondrial membrane 20(TOM 20) expression and increased DLAT oligomers. Moreover, the above changes of MELK to HCC were abolished by elesclomol. In conclusion, MELK enhanced the levels of the cuproptosis-related signature(CRS) gene DLAT (especially the proportion of DLAT monomer) by activating the PI3K/mTOR pathway, thereby promoting elesclomol drug resistance, altering mitochondrial function, and ultimately promoting HCC progression.© 2023. The Author(s).