Selenium photosensitizer PDSe-8 degrades STEAP3 and triggers ferroptosis in glioblastoma cells

Resistance to apoptosis limits the efficacy of many cancer therapies, and photodynamic therapy can engage other cell death pathways such as ferroptosis. The direct molecular targets of most photosensitizers remain undefined. In a paper in Proceedings of the National Academy of Sciences, the authors describe a class of selenium-containing D–π–A photosensitizers, PDSe-1 to PDSe-11. pnas.orgProceedings of the National Academy of Sciencespnas.orgOpen source ↗ The lead compound, PDSe-8, has favourable photophysical properties and hypoxia-tolerant phototoxicity with an IC50 of 53 nM.

The effect depends on concentration. Low doses of PDSe-8 trigger apoptosis through p38 MAPK signaling, while higher doses activate ferroptosis. Competitive chemoproteomics identified the metalloreductase STEAP3 as a direct molecular target of light-activated PDSe-8.

Upon photoirradiation, PDSe-8 photodegrades STEAP3 in glioblastoma cells. This activates p53, impairs the SLC7A11–GPX4 antioxidant axis and drives lethal lipid peroxidation, leading to ferroptotic cell death. According to the authors, the compound showed antitumor efficacy against U87MG glioblastoma both in vitro and in vivo. They propose STEAP3 as a key molecular target for photodynamic therapy.