心脏毒性
KEAP1型
斑马鱼
阿霉素
药理学
化学
程序性细胞死亡
体内
癌症研究
细胞生物学
细胞凋亡
生物化学
生物
医学
毒性
内科学
生物技术
化疗
转录因子
基因
作者
C. Liu,Yingchao Wang,Yi‐Xin Zeng,Zhijun Kang,Hong Zhao,Kun Qi,Hongzhi Wang,Lu Zhao,Yi Wang
标识
DOI:10.1002/advs.202301136
摘要
Doxorubicin-induced cardiomyopathy (DIC) brings tough clinical challenges as well as continued demand in developing agents for adjuvant cardioprotective therapies. Here, a zebrafish phenotypic screening with deep-learning assisted multiplex cardiac functional analysis using motion videos of larval hearts is established. Through training the model on a dataset of 2125 labeled ventricular images, ZVSegNet and HRNet exhibit superior performance over previous methods. As a result of high-content phenotypic screening, cyanidin chloride (CyCl) is identified as a potent suppressor of DIC. CyCl effectively rescues cardiac cell death and improves heart function in both in vitro and in vivo models of Doxorubicin (Dox) exposure. CyCl shows strong inhibitory effects on lipid peroxidation and mitochondrial damage and prevents ferroptosis and apoptosis-related cell death. Molecular docking and thermal shift assay further suggest a direct binding between CyCl and Keap1, which may compete for the Keap1-Nrf2 interaction, promote nuclear accumulation of Nrf2, and subsequentially transactivate Gpx4 and other antioxidant factors. Site-specific mutation of R415A in Keap1 significantly attenuates the protective effects of CyCl against Dox-induced cardiotoxicity. Taken together, the capability of deep-learning-assisted phenotypic screening in identifying promising lead compounds against DIC is exhibited, and new perspectives into drug discovery in the era of artificial intelligence are provided.
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