线粒体自噬是抗肿瘤药物开发的重要靶点。设计并制备了一系列针对 PTEN 诱导的推定激酶 1 (PINK1)/Parkin 介导的线粒体自噬的环吡酮 (CPX) 铂 (IV) 杂合体作为抗肿瘤药物。筛选出具有顺铂核心的双 CPX 铂（IV）复合物作为候选物，该复合物在体外和体内均显示出良好的抗肿瘤活性。从机制上讲，它对肿瘤细胞造成严重的DNA损伤。然后，伴随线粒体膜去极化和活性氧生成，诱导显着的线粒体损伤，从而通过 Bcl-2/Bax/Caspase3 途径进一步促进细胞凋亡。此外，线粒体自噬是通过PINK1/Parkin/P62/LC3轴引发的，对促进肿瘤细胞的凋亡表现出积极的影响。免疫检查点程序性细胞死亡配体-1（PD-L1）的阻断增强了抗肿瘤免疫力，进一步增加了肿瘤中T细胞的密度。随后，通过抑制肿瘤内的血管生成来抑制肿瘤细胞的转移。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Mitophagy is an important target for antitumor drugs development. A series of ciclopirox (CPX) platinum(IV) hybrids targeting PTEN induced putative kinase 1 (PINK1)/Parkin mediated mitophagy were designed and prepared as antitumor agents. The dual CPX platinum(IV) complex with cisplatin core was screened out as a candidate, which displayed promising antitumor activities both in vitro and in vivo. Mechanistically, it caused serious DNA damage in tumor cells. Then, remarkable mitochondrial damage was induced accompanied by the mitochondrial membrane depolarization and reactive oxygen species generation, which further promoted apoptosis through the Bcl-2/Bax/Caspase3 pathway. Furthermore, mitophagy was ignited via the PINK1/Parkin/P62/LC3 axis, and exhibited positive influence on promoting the apoptosis of tumor cells. The antitumor immunity was boosted by the block of immune check point programmed cell death ligand-1 (PD-L1), which further increased the density of T cells in tumors. Subsequently, the metastasis of tumor cells was inhibited by inhibiting angiogenesis in tumors.Copyright © 2024 Elsevier Inc. All rights reserved.