Pt(IV)-Deferasirox Prodrug Combats DNA Damage Repair by Regulating RNA N6-Methyladenosine Methylation

DNA damage repair is considered to be an important mechanism of cisplatin resistance, and the roles of iron homeostasis in action mechanisms of cisplatin have not been studied yet. Herein, a Pt(IV) prodrug (DFX-Pt) integrating cisplatin and the clinical oral iron-chelating agent deferasirox (DFX) is found to be highly active toward cisplatin-insensitive triple-negative breast cancer cells both in vitro and in vivo. RNA-sequencing shows that DFX-Pt can downregulate genes related to the double-strand break (DSB) damage pathway significantly. DFX-Pt can reduce cellular free iron, regulate the expression of the RNA demethylase, and elevate the levels of RNA N6-methyladenosine (m6A), which degrades the DSB-related genes in an m6A-dependent manner. In all, we first reveal the roles of RNA modification in mechanisms of combating DNA damage repair and show that the combination of iron homeostasis intervention may bring new treatment regimens for cisplatin resistance.