Related Experiment Video
Updated: Mar 3, 2026
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
DPP4 suppresses pancreatic cancer growth by enhancing ferroptosis sensitivity through stabilization of ACSL4
Xiang Zhou1, Lingming Kong1, Baofu Zhang1
1Department of Hepato-Pancreatic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Abstract:
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.
Insights
Dipeptidyl peptidase-4 (DPP4) promotes ferroptosis in pancreatic cancer by stabilizing ACSL4. Targeting the DPP4-ACSL4 pathway may enhance ferroptosis therapies for pancreatic ductal adenocarcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with few treatment options.
- Ferroptosis, a regulated cell death pathway, presents a potential therapeutic strategy for PDAC.
- The role of dipeptidyl peptidase-4 (DPP4) in PDAC ferroptosis remains unclear.
Purpose of the Study:
- To investigate the function of DPP4 in regulating ferroptosis in PDAC.
- To elucidate the interaction between DPP4 and long-chain acyl-CoA synthetase 4 (ACSL4) in PDAC.
- To explore the DPP4-ACSL4 axis as a potential therapeutic target for PDAC.
Main Methods:
- Analysis of DPP4 expression in PDAC tissues and cell lines.
- In vitro studies involving DPP4 overexpression and knockdown in PDAC cells.
- Assessment of ferroptosis markers, cell cycle, mitochondrial function, and lipid peroxidation.
- In vivo studies using an orthotopic PDAC mouse model.
- Co-immunoprecipitation assays to confirm DPP4-ACSL4 binding.
Main Results:
- DPP4 expression is downregulated in PDAC tissues.
- DPP4 overexpression inhibits PDAC cell proliferation, induces cell cycle arrest, impairs mitochondrial respiration, and sensitizes cells to ferroptosis.
- DPP4 directly binds to ACSL4, stabilizing it and promoting lipid peroxidation.
- DPP4 deficiency reduces erastin-induced ferroptosis and tumor growth in vivo.
- ACSL4 knockdown abrogates DPP4-mediated ferroptosis and lipid ROS accumulation.
Conclusions:
- DPP4 acts as a positive regulator of ferroptosis in PDAC by stabilizing ACSL4.
- The DPP4-ACSL4 axis is crucial for ferroptosis induction in PDAC.
- Targeting the DPP4-ACSL4 pathway offers a promising strategy to enhance ferroptosis-based treatments for PDAC.
