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

ABSTRACT 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.