Targeting of STEAP3 by a selenium D-π-A photosensitizer that activates ferroptosis.

PDSe-8, a selenium D-π-A photosensitizer, targets STEAP3 in glioblastoma cells and enables hypoxia-tolerant phototoxicity with an IC 50 of 53 nM.

• Why it matters: Apoptosis resistance limits many cancer treatments, and most photosensitizers lack defined molecular targets for nonapoptotic death pathways like ferroptosis.
• What they did: The authors synthesized PDSe-1 to PDSe-11, selected PDSe-8, and used competitive chemoproteomics to identify STEAP3 as a direct light-activated target. They then showed PDSe-8 photoirradiation photodegrades STEAP3 in U87MG cells.
• The result: Light-activated PDSe-8 switches cell death programs: low doses trigger p38 MAPK-linked apoptosis, while higher doses activate ferroptosis via p53 activation, SLC7A11-GPX4 axis impairment, and lethal lipid peroxidation, yielding antitumor efficacy in vitro and in vivo.

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