DUSP5 regulates ferroptosis in pancreatic cancer by down-regulating SCD1 expression via ERK1/2

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with limited therapeutic options. The Ras/Raf/MEK/ERK signaling pathway is critically involved in PDAC progression, yet targeting its downstream effectors remains challenging. DUSP5, a nuclear phosphatase that dephosphorylates ERK1/2, has emerged as a potential tumor suppressor, but its role in PDAC and underlying mechanisms are poorly understood. In this study, DUSP5 is significantly downregulated in PDAC tissues compared to adjacent normal tissues (ANTs) and correlated with a favorable prognosis. Overexpression of DUSP5 inhibits PDAC cell proliferation in vitro and in vivo. Mechanistically, DUSP5 physically interacts with ERK1/2 in the nucleus, leading to ERK1/2 dephosphorylation and inactivation, which downregulates SCD1 expression, a key enzyme converting saturated fatty acids to monounsaturated fatty acids (MUFAs). Reduced SCD1 levels decrease MUFA synthesis (C16:1 and C18:1), increase lipid peroxidation, and induce mitochondrial dysfunction characteristic of ferroptosis. Rescue experiments confirm that supplementation with MUFAs or ferroptosis inhibitors reverses DUSP5-mediated growth inhibition. In conclusion, this study identifies DUSP5 as a novel suppressor of PDAC progression that induces ferroptosis via the ERK1/2/SCD1 axis. Targeting the DUSP5/ERK1/2/SCD1 pathway may represent a promising therapeutic strategy for PDAC.