March 3, 2026Open Access

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

Key Points

RS-1 induces significant GPX4 degradation, leading to elevated lipid peroxidation and cell death through ferroptosis.
In HT1080 cells, RS-1 demonstrates a DC50 of 8.9 nM for GPX4 degradation, reliant on the ubiquitin-proteasome system.
In vivo analysis shows RS-1 achieves 80.5% tumor growth inhibition against 4T1 murine mammary carcinoma.
These findings indicate the potential of RS-1 as a therapeutic agent targeting ferroptosis for cancer treatment.

Abstract

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 (DC50 = 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.

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

Key Points

Abstract

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