Cisplatin Conjugated with Vinylsulfonamide Cross-Links Pyruvate Kinase M2 to Trigger Ferroptosis

Abstract Cisplatin serves as a first-line chemotherapeutic agent due to its DNA binding property. However, this intrinsic electrophilicity drives off-target interactions with proteins, which compromises anticancer efficacy, and also suggests the presence of unexplored targets. To identify platinum-binding proteins, a class of platinum(II) complexes containing a covalent vinylsulfonamide group were designed to provide stronger affinity for target engagement. By using competitive chemical proteomics technology, pyruvate kinase M2 (PKM2) was identified as the direct target of Pt1. The intracellular binding involved the recognition of the Cys49 pocket via cis-platinum moiety, which was strengthened by the synergistic event of platinum-centered ligand exchange and vinylsulfonamide-mediated covalent anchoring. This effective multimodal interaction disrupted PKM2 oligomerization and promoted its nuclear translocation. Subsequently, Pt1 induced ferroptosis via the PKM2-HMOX1 axis, further enhanced by mitochondrial oxidative stress. In xenograft models, Pt1 exhibited antitumor efficacy comparable to that of cisplatin, along with lower hepatotoxicity. This study presents a cisplatin conjugate that induces ferroptosis through intramolecular protein cross-linking, providing a synergistic coordination-covalent strategy for nonclassical platinum-based therapeutics.