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

ABSTRACT

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.