Targeted extracellular degradation of LRP8 promotes ferroptosis in cancer cells.

Targeted degradation of LRP8 reduces GPX4 levels by 50%, sensitizing cancer cells to ferroptosis and revealing a new vulnerability in tumor antioxidant defenses.

• Why it matters: Cancer cells depend on antioxidant systems like GPX4 to survive oxidative stress, but current methods to disrupt these defenses are limited, hindering effective therapies.
• What they did: Researchers used bispecific KineTACs to direct LRP8 to lysosomes for degradation, decreasing selenoproteins including GPX4 in cancer cells, thereby lowering their ferroptosis threshold.
• The result: This approach demonstrates that extracellular protein degradation can reprogram intracellular dependencies, offering a novel strategy to overcome therapy resistance by targeting nutrient uptake pathways.