Cisplatin is an efficient chemotherapeutic agent for various solid tumors, but its usage is restricted by nephrotoxicity. A single dose of cisplatin can cause acute kidney injury (AKI), which is characterized by rapid reduction in kidney function. However, the current therapies, such as hydration, are limited. It is vital to develop novel therapeutic reagents that have both anticancer and renoprotective properties. The objective of this study was to determine whether ammonium tetrathiomolybdate (TM), a copper chelator used to treat cancer and disorders of copper metabolism, may offer protection against cisplatin-induced AKI. In this study, we demonstrated that TM treatment had antioxidative effects and mitigated cisplatin-induced AKI both in vivo and in vitro. Mechanically, TM inhibited NRF2 ubiquitination, which activated the NRF2 pathway in HK-2 cells and promoted the expression of target genes. It should be noted that the protective effect conferred by TM against cisplatin was compromised by the knockdown of the NRF2 gene. Furthermore, TM selectively activated the NRF2 pathways in the liver and kidney. The current study provided evidence for additional clinical applications of TM by showing that it activates NRF2 and has a favorable therapeutic impact on cisplatin-induced AKI.

顺铂是治疗多种实体瘤的有效化疗药物，但其使用受到肾毒性的限制。单剂量顺铂可引起急性肾损伤（AKI），其特点是肾功能迅速下降。然而，目前的疗法（例如水合）是有限的。开发具有抗癌和肾脏保护特性的新型治疗试剂至关重要。本研究的目的是确定四硫代钼酸铵 (TM)（一种用于治疗癌症和铜代谢紊乱的铜螯合剂）是否可以提供针对顺铂诱导的 AKI 的保护作用。在这项研究中，我们证明了 TM 治疗具有抗氧化作用，并在体内和体外减轻顺铂诱导的 AKI。机械上，TM抑制NRF2泛素化，从而激活HK-2细胞中的NRF2通路并促进靶基因的表达。值得注意的是，TM 对顺铂的保护作用因 NRF2 基因的敲低而受到损害。此外，TM选择性激活肝脏和肾脏中的NRF2通路。目前的研究表明 TM 可以激活 NRF2，并对顺铂诱导的 AKI 具有良好的治疗作用，为 TM 的其他临床应用提供了证据。