Pyroptosis-Inducing Platinum(IV) Prodrugs via GSDME Pathway for Chemoimmunotherapy and Metastasis Inhibition in Triple-Negative Breast Cancer.

ABSTRACT: Pyroptosis has attracted significant attention for its role in cancer chemotherapy and immunotherapy. However, few drugs have been reported to induce pyroptosis via the Caspase-3/gasdermin E (GSDME) pathway. Herein, three novel Pt^IV prodrugs, MRP, DRP, and HRP are rationally designed by conjugating DNA methyltransferase (DNMT) inhibitor (RG108) and/or histone deacetylase (HDAC) inhibitor (PhB) to the Pt^IV center. These prodrugs can be easily reduced to cisplatin (CDDP) due to the high glutathione (GSH) levels in tumors, liberating the coordinated ligands. Released RG108 reactivates the GSDME gene and reduces pyroptosis in low GSDME-expressing tumor cells. Meanwhile, PhB-induced chromatin loosening enhances CDDP-DNA binding, which not only increases Caspase-3 expressio

SUBMITTER: Yang X 

PROVIDER: S-EPMC12362741 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature