DUSP1 Blocks autophagy-dependent ferroptosis in pancreatic cancer

Abstract. Ferroptosis is a oxidative damage-dependent form of regulated cell death that has become an emerging target for disease prevention and treatment. Here, we show that dual-specificity phosphatase 1 (DUSP1), a phosphatase playing multiple roles in stress-signaling pathways, is a new repressor of ferroptosis in human pancreatic cancer cells. Several classical ferroptosis activators (eg, erastin and RSL3) induce the expression of DUSP1, but not other members of DUSP, which depends on extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). Moreover, shRNA-mediated DUSP1 knockdown increases the anticancer activity of ferroptosis activators in pancreatic cancer cells through activating lipid peroxidation in vitro and in vivo. Importantly, DUSP1-mediated autophagy is responsible for lipid peroxidation-mediated ferroptotic cell death. Thus, the DUSP1-related ferroptotic pathway may represent a potential target for therapeutic intervention in pancreatic cancer.