論文 - 詳細
| RRC ID | 87639 |
|---|---|
| 著者 | Jiang H, Satoh Y, Yamamura R, Ooshio T, Luo Y, Hai H, Otsuka T, Hata S, Sato R, Hirata T, Osawa T, Goda K, Sonoshita M. |
| タイトル | Inhibition of NAD-GPx4 axis and MEK triggers ferroptosis to suppress pancreatic ductal adenocarcinoma. |
| ジャーナル | Mol Ther |
| Abstract |
Pancreatic ductal adenocarcinoma (PDAC) ranks among the most lethal malignancies, highlighting the critical need for innovative therapeutic strategies. In this study, we examined the roles of nicotinamide adenine dinucleotide (NAD) synthesis pathway in PDAC. Targeting the NAD synthesis pathway significantly mitigated lethality in a Drosophila model that recapitulated the PDAC genotype. Within this pathway, we identified Glutathione peroxidase 4 (GPx4) as a critical effector responsible for scavenging reactive oxygen species (ROS). The combined application of GPx4 and Mitogen-activated protein kinase kinase (MEK) inhibitors, namely ML210 and trametinib, respectively, reduced lethality and tumor-like phenotypes in these flies. Notably, this combination treatment synergistically suppressed the proliferation of human PDAC cells and their corresponding xenografts in mice by inducing ROS accumulation, which triggered ferroptosis. These results suggest that inducing ferroptosis could represent a promising therapeutic strategy for PDAC. |
| 巻・号 | 33(9) |
| ページ | 4618-4635 |
| 公開日 | 2025-9-3 |
| DOI | 10.1016/j.ymthe.2025.05.037 |
| PII | S1525-0016(25)00407-1 |
| PMID | 40450524 |
| PMC | PMC12432899 |
| MeSH | Animals Carcinoma, Pancreatic Ductal* / drug therapy Carcinoma, Pancreatic Ductal* / genetics Carcinoma, Pancreatic Ductal* / metabolism Carcinoma, Pancreatic Ductal* / pathology Cell Line, Tumor Cell Proliferation / drug effects Disease Models, Animal Ferroptosis* / drug effects Humans Mice Mitogen-Activated Protein Kinase Kinases* / antagonists & inhibitors Mitogen-Activated Protein Kinase Kinases* / metabolism NAD* / metabolism Pancreatic Neoplasms* / drug therapy Pancreatic Neoplasms* / metabolism Pancreatic Neoplasms* / pathology Phospholipid Hydroperoxide Glutathione Peroxidase* / antagonists & inhibitors Phospholipid Hydroperoxide Glutathione Peroxidase* / genetics Phospholipid Hydroperoxide Glutathione Peroxidase* / metabolism Protein Kinase Inhibitors / pharmacology Pyridones / pharmacology Pyrimidinones / pharmacology Reactive Oxygen Species / metabolism Xenograft Model Antitumor Assays |
| IF | 8.986 |
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| ショウジョウバエ | |