Dai Enyong, Han Leng, Liu Jiao, Xie Yangchun, Zeh Herbert J, Kang Rui, Bai Lulu, Tang Daolin
Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130031, China.
Protein Modification and Degradation Lab, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
Nat Commun. 2020 Dec 11;11(1):6339. doi: 10.1038/s41467-020-20154-8.
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.
铁死亡是一种最近才被认识到的细胞死亡形式，它依赖于铁介导的氧化损伤。在此，我们评估高铁饮食或缺失Gpx4（一种据报道作为重要铁死亡抑制因子的抗氧化酶）对患有蓝菌素或L-精氨酸诱导的胰腺炎的小鼠胰腺以及自发胰腺导管腺癌（PDAC）的致癌性Kras小鼠模型的影响。我们发现，高铁饮食或Gpx4缺失均会促进8-羟基鸟嘌呤（8-OHG）释放，从而激活TMEM173/干扰素基因刺激蛋白（STING）依赖性DNA传感途径，这会导致Kras驱动的小鼠PDAC过程中巨噬细胞浸润和激活。因此，给予liproxstatin-1（一种铁死亡抑制剂）、氯磷体介导的巨噬细胞清除或对8-OHG-TMEM173途径进行药理学和遗传学抑制，均可抑制Kras驱动的小鼠胰腺肿瘤发生。GPX4也是PDAC患者的一个预后标志物。这些发现为小鼠PDAC肿瘤发生过程中的铁死亡损伤提供了病理学和机制方面的见解。
