Disruption of iron homeostasis sensitizes pancreatic cancer to irreversible electroporation.

Irreversible electroporation (IRE) is an ablative treatment for pancreatic cancer. It utilizes high-intensity pulsed electric field (PEF) to eliminate cancer cells by irreversibly disrupting cell membranes. However, PEF intensity is distributed unevenly; and cancer cells may survive in regions where it falls below the threshold of complete ablation. We find that iron-base metal organic framework nanoparticles (MOF-Fe) sensitize pancreatic cancer cells to PEF by inducing iron overload and ferroptosis. But their efficacy is diminished by the upregulation of ferritin heavy chain 1 (FTH1), a cellular response to restore iron homeostasis. C20U4V, a proteolysis targeting chimera (PROTAC) derived from arachidonic acid, degrades FTH1 and potentiates MOF-Fe-induced ferroptosis. It is then encapsulated in reactive oxygen species (ROS)-responsive micelles. The resulting M-C20U4V, when combined with MOF-Fe, efficiently induces ferroptosis and boosts PEF ablation efficacy. Therefore, disruption of iron homeostasis represents a potential strategy to lower the risk of tumor recurrence after IRE.