| Autor: |
Dai E; Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130031, China., Han L; Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130031, China., Liu J; Protein Modification and Degradation Lab, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, China., Xie Y; Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China., Zeh HJ; Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA., Kang R; Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA., Bai L; Department of Pediatric Hematology, First Hospital of Jilin University, Changchun, Jilin, 130021, China. bailulu@jlu.edu.cn., Tang D; Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA. daolin.tang@utsouthwestern.edu. |
| Abstrakt: |
Ferroptosis is a more recently recognized form of cell death that relies on iron-mediated oxidative damage. Here, we evaluate the impact of high-iron diets or depletion of Gpx4, an antioxidant enzyme reported as an important ferroptosis suppressor, in the pancreas of mice with cerulean- or L-arginine-induced pancreatitis, and in an oncogenic Kras murine model of spontaneous pancreatic ductal adenocarcinoma (PDAC). We find that either high-iron diets or Gpx4 depletion promotes 8-OHG release and thus activates the TMEM173/STING-dependent DNA sensor pathway, which results in macrophage infiltration and activation during Kras-driven PDAC in mice. Consequently, the administration of liproxstatin-1 (a ferroptosis inhibitor), clophosome-mediated macrophage depletion, or pharmacological and genetic inhibition of the 8-OHG-TMEM173 pathway suppresses Kras-driven pancreatic tumorigenesis in mice. GPX4 is also a prognostic marker in patients with PDAC. These findings provide pathological and mechanistic insights into ferroptotic damage in PDAC tumorigenesis in mice. |
