Abstract：
The clinical application of the therapeutic approach in myelodysplastic syndromes (MDS) remains an insurmountable challenge for the high propensity for progressing to acute myeloid leukemia and predominantly affecting elderly individuals. Thus, the discovery of molecular mechanisms underlying the regulatory network of different programmed cell death holds great promise for the identification of therapeutic targets and provides insights into new therapeutic avenues. Herein, we found that disulfiram/copper (DSF/Cu) significantly repressed the cell viability, increased reactive oxygen species (ROS) accumulation, destroyed mitochondrial morphology, and altered oxygen consumption rate. Further studies verified that DSF/Cu induces cuproptosis, as evidenced by the depletion of glutathione (GSH), aggregation of lipoylated DLAT, and induced loss of Fe-S cluster-containing proteins, which could be rescued by tetrathiomolybdate and knockdown of ferredoxin 1 (FDX1). Additionally, GSH contributed to the tolerance of DSF/Cu-mediated cuproptosis, while pharmacological chelation of GSH triggered ROS accumulation and sensitized cell death. The xCT-GSH-GPX4 axis is the ideal downstream component of ferroptosis that exerts a powerful protective mechanism. Notably, classical xCT inhibitors were capable of leading to the catastrophic accumulation of ROS and exerting synergistic cell death, while xCT overexpression restored these phenomena. Simvastatin, an inhibitor of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase, has beneficial effects in repurposing for inhibiting GPX4. Similarly, the combination treatment of DSF/Cu and simvastatin dramatically decreased the expression of GPX4 and Fe-S proteins, ultimately accelerating cell death. Moreover, we identified that the combination treatment of DSF/Cu and simvastatin also had a synergistic antitumor effect in the MDS mouse model, with the reduced GPX4, increased COX-2 and accumulated lipid peroxides. Overall, our study provided insight into developing a novel synergistic strategy to sensitize MDS therapy by targeting ferroptosis and cuproptosis.
摘要：
治疗方法在骨髓增生异常综合征（MDS）中的临床应用对于发展为急性髓细胞性白血病并主要影响老年人的高倾向仍然是一个无法克服的挑战。因此，不同程序性细胞死亡调控网络的分子机制的发现为识别治疗靶点带来了巨大希望，并为新的治疗途径提供了见解。在这里，我们发现双硫仑/铜（DSF/Cu）显著抑制细胞活力，增加活性氧（ROS）积累，线粒体形态被破坏，改变了耗氧率.进一步的研究证实DSF/Cu诱导角化，正如谷胱甘肽（GSH）的消耗所证明的那样，脂化DLAT的聚集，并诱导含Fe-S簇蛋白的损失，可以通过四硫钼酸盐和铁氧还蛋白1（FDX1）的敲低来挽救。此外,GSH有助于DSF/Cu介导的角化凋亡的耐受性，而GSH的药理螯合引发ROS积累和致敏细胞死亡。xCT-GSH-GPX4轴是铁性凋亡的理想下游成分，具有强大的保护机制。值得注意的是,经典的xCT抑制剂能够导致ROS的灾难性积累并产生协同细胞死亡，而xCT过表达恢复了这些现象。辛伐他汀,HMG-CoA（3-羟基-3-甲基戊二酰辅酶A）还原酶的抑制剂，在再利用抑制GPX4方面具有有益作用。同样，DSF/Cu和辛伐他汀联合治疗可显著降低GPX4和Fe-S蛋白的表达,最终加速细胞死亡。此外，我们发现，在MDS小鼠模型中，DSF/Cu和辛伐他汀的联合治疗也具有协同抗肿瘤作用，随着GPX4的减少，COX-2增加和脂质过氧化物的积累。总的来说,我们的研究提供了一种新的协同策略，通过靶向铁性凋亡和角化凋亡来提高MDS治疗的敏感性。
