Glutathione peroxidase 4 (GPX4) is recognized as a critical regulator of ferroptosis, playing a significant role in lipid and amino acid metabolism, as well as influencing cellular aging, oncogenesis, and cell death [1]. Targeting GPX4-mediated ferroptosis presents a promising therapeutic strategy, particularly in the treatment of cancer [2]. Despite its potential, GPX4’s flat surface presents significant challenges, as it lacks distinct druggable pockets (Fig. 1A). Current inhibitors of GPX4 with cellular activity typically covalently bind...