Endoplasmic Reticulum-Targeting Quinazolinone-Based Lipophilic Probe for Specific Photoinduced Ferroptosis and Its Induced Lipid Dynamic Regulation

作者：Zhiming Xing, Jiangyu Yan, Yongxiang Miao, Yawen Ruan, Haojun Yao, Youkang Zhou, Yingqun Tang, Guorui Li, Zhibin Song, Yiyuan Peng, Jing Huang · 发表于：Journal of Medicinal Chemistry · 年份：2024 · DOI：10.1021/acs.jmedchem.3c01652 · 被引用次数：27 · 研究领域：Ferroptosis and cancer prognosis、RNA modifications and cancer、Drug Transport and Resistance Mechanisms

Lethal lipid peroxidation caused by reactive oxygen species occurs in different types of programmed cell death, especially in ferroptosis. Ferroptosis inducers, which serve as small-molecule probes, can provide insight into the mechanism of ferroptosis and facilitate drug discovery. The classical ferroptosis inducers indirectly lead to lipid peroxidation; thus, it is difficult to explore lipid regulation during the ferroptotic process. In this study, we designed two quinazolinone-based lipophilic probes BODIQPy-TPA and QPy-TPA, which proved to directly induce lipid peroxidation by light irradiation in vitro. The probe BODIQPy-TPA, which was mainly distributed in the endoplasmic reticulum (ER), specifically triggered ferroptosis in B16 and HepG2 cells upon light irradiation. As a comparison, the probe QPy-TPA, which was mainly distributed in lipid droplets (LDs), induced cell death by a nonferroptotic pathway. Further lipidomic analysis revealed that these two probes caused different patterns of lipid regulation and lipid peroxidation, suggesting that ferroptosis might activate distinct lipid regulation.