Precision Ferroptosis Amplification via SLC7A11‐Directed Proteasomal Degradation for Enhanced Cancer Therapy

Ferroptosis is a regulated cell death pathway driven by the iron-dependent accumulation of reactive oxygen species (ROS) and lipid hydroperoxides. A major factor limiting the effectiveness of ferroptosis induction is the antioxidant activity of glutathione peroxidase 4 (GPX4). Herein, we reported SLC7A11-targeting proteolysis targeting chimeras (PROTACs) to deplete GPX4 and to augment oxidative stress within cancer cells. A bifunctional PROTAC, namely dSLC7A11, ws designed by conjugating the SLC7A11 inhibitor sulfasalazine to the CRBN ligand pomalidomide via an alkyl linker. The rational designed chimera effectively induced ubiquitin-mediated degradation of SLC7A11. Consequently, this inactivated cystine/glutamate antiporter (System Xc^-), depleted GPX4, and amplified oxidative stress in cancer cells. Notably, dSLC7A11 exhibited superior antitumor efficacy over sulfasalazine alone, and achieved an effect of suppressing tumor growth by >65% in vivo. This study presented a SLC7A11-targeting PROTAC that disrupts the cellular antioxidant defense system, thus establishing a novel PROTAC-based approach for potent ferroptosis induction in cancer therapy.