Myoferlin targeting triggers mitophagy and primes ferroptosis in pancreatic cancer cells. Investigation of STAT3 involvement.

Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer-related deaths worldwide. Myoferlin is a protein implicated in membrane fusion and in receptor recycling. It allows the formation of vesicles for the trafficking in cells. In PDAC, myoferlin is overexpressed in high grades in comparison to low grades. We used an innovative small compound (WJ460) to target myoferlin in PDAC cell lines and reported the triggering of an iron-dependent cell death, namely ferroptosis, considered as an alternative to apoptosis in cancer cells. Owing to the role of STAT3 in iron homeostasis, we decided to explore this signaling pathway upon myoferlin depletion and pharmacological targeting.