DPP4 suppresses pancreatic cancer growth by enhancing ferroptosis sensitivity through stabilization of ACSL4.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited therapeutic options. This study investigated the role of dipeptidyl peptidase-4 (DPP4) in regulating ferroptosis through its interaction with long-chain acyl-CoA synthetase 4 (ACSL4) in PDAC. DPP4 expression was significantly downregulated in PDAC tumor tissues compared with paired adjacent non-tumorous tissues from 56 patients. In vitro, DPP4 overexpression in PDAC cell lines inhibited cell proliferation, induced G1-S cell cycle arrest, impaired mitochondrial respiration, and markedly sensitized cells to erastin-induced ferroptosis. This sensitization was characterized by elevated unstable iron pools, increased lipid reactive oxygen species (ROS) and malondialdehyde levels, decreased glutathione and GPX4 expression, and ferroptotic mitochondrial morphology. These effects were specifically rescued by ferroptosis inhibitors. In an orthotopic PDAC mouse model, erastin treatment suppressed tumor growth and proliferation more effectively in wild-type mice than in DPP4-knockout mice, with reduced lipid peroxidation in knockout tumors. Mechanistically, DPP4 directly bound ACSL4, stabilized ACSL4 protein by inhibiting its ubiquitin-mediated degradation, and promoted ACSL4-dependent lipid peroxidation. ACSL4 knockdown rescued DPP4 overexpression-induced ferroptosis and lipid ROS accumulation. These results demonstrate that DPP4 acts as a positive regulator of ferroptosis in PDAC by stabilizing ACSL4, highlighting the DPP4-ACSL4 axis as a potential therapeutic target to enhance ferroptosis-based strategies against this aggressive cancer.