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

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.