BioinspiredConstruction of Cu–Fe BimetallicMultienzyme Mimetics as Co-Inducers of Cuproptosis and Ferroptosis

作者：Qing‐Hua Shen, Long‐Bo Yu, Shan-Ming Yao, Zhiyuan Li, Qiqi Zhang, Peng Wang, Cai‐Ping Tan · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c01174 · 被引用次数：5 · 研究领域：RNA modifications and cancer、Trace Elements in Health、Ferroptosis and cancer prognosis

Abstract Metalloenzyme mimics based on small molecules are valuable therapeutic candidates, but there are few reports on their mechanism of action. Inspired by natural enzymes, we designed two Cu–Fe bimetallic multienzyme mimetics (CuFc1 and CuFc2). Due to the coordination of the bimetallic centers, CuFc1 exhibits mimetic activities for multiple enzymes, including peroxidase (POD), catalase (CAT), superoxide dismutase (SOD), and glutathione oxidase (GSHOx). CuFc1 can catalyze cascade reactions from •O2– and H2O2 to O2 and •OH, which leads to a storm of reactive oxygen species and causes cuproptosis and ferroptosis in cancer cells simultaneously. As CuFc1 treatment upregulates the expression of PD-L1, it acts synergistically with the PD-L1 inhibitor (BMS-1) to remodel the tumor immune microenvironments and stimulates intense anticancer immune responses in vivo. In summary, through reasonable molecular design, we first demonstrate the enormous potential of metallo small molecule-based multienzyme mimics in cancer immunotherapy.