Pancreatic ductal adenocarcinoma (PDA) cells reprogram both mitochondrial and lysosomal functions to sustain growth.
At the same time, this metabolic rewiring leads to significant free radical dyshomeostasis. Although this imbalance is compensated by enhanced detoxification mechanisms, it also creates a potential vulnerability.
In this study, we demonstrate that PDA cells are highly sensitive to inhibition of the mevalonate pathway (MVP), which supports the biosynthesis of critical antioxidant intermediates and protects against ferroptosis. We exploited this susceptibility using selenoorganic compounds, including dibenzyl diselenide (DBDS), which exhibits potent pro-oxidant properties and inhibits tumor growth both in vitro and in vivo.
Treatment with DBDS triggers iron mobilization from mitochondria, leading to uncontrolled lipid peroxidation. Finally, we show that DBDS and statins act synergistically to promote ferroptosis, and we provide evidence that the combined treatment represents a promising therapeutic strategy against PDA.
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