RS-1: A Novel Hydrophobic Tagging GPX4 Degrader Inducing Ferroptosis and Suppressing Tumor Growth.

Glutathione peroxidase 4 (GPX4), a critical regulator of ferroptosis, represents an attractive therapeutic target in oncology. Here, we report the design, synthesis, and biological evaluation of RS-1, a hydrophobic tagging (HyT)-mediated GPX4 degrader. RS-1 induced dose- and time-dependent GPX4 degradation in HT1080 fibrosarcoma cells (DC(50) = 8.9 nM), mechanistically dependent on the ubiquitin-proteasome system, as confirmed by MG-132 cotreatment. Ferrostatin-1 (Fer-1) rescued RS-1-induced cell death, validating ferroptosis as the primary mechanism. Consistent with GPX4 loss, RS-1 elevated lipid peroxidation markers (reactive oxygen species (ROS) and malondialdehyde (MDA)) in HT1080 cells. In vivo, RS-1 demonstrated potent antitumor efficacy in a 4T1 murine mammary carcinoma model, achieving 80.5% tumor growth inhibition (TGI). These findings establish RS-1 as a novel GPX4-targeted degrader with translational potential, offering a promising strategy to exploit ferroptosis in cancer therapy.