Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway

Enyong Dai, Leng Han, Jiao Liu, Yangchun Xie, Herbert J. Zeh, Rui Kang, Lulu Bai () and Daolin Tang ()
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Enyong Dai: China-Japan Union Hospital of Jilin University
Leng Han: China-Japan Union Hospital of Jilin University
Jiao Liu: Third Affiliated Hospital of Guangzhou Medical University
Yangchun Xie: Central South University
Herbert J. Zeh: UT Southwestern Medical Center
Rui Kang: UT Southwestern Medical Center
Lulu Bai: First Hospital of Jilin University
Daolin Tang: UT Southwestern Medical Center

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-20154-8

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