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.

The ongoing coronavirus disease 2019 (COVID-19) pandemic is a serious public health crisis, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The major structural protein of SARS-CoV-2 is spike (S) protein, and its ectodomain is divided into two subunits, S1 and S2, which are responsible for receptor binding and membrane fusion, respectively. Like the closely related severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) as entry receptor 1. S protein binds ACE2 through its receptor-binding domain (RBD) located within S1 subunit. Thus far, a number of SARS-CoV-2 vaccine candidates derived from different vaccine platforms, including DNA vaccine, mRNA vaccine, inactivated whole virus vaccine, and adenovirus-vectored vaccine, have rapidly progressed into clinical trials 2,3. One of the challenges in developing vaccines for coronaviruses is the potential vaccineinduced immune enhancement of disease 4,5. Antibodies raised against inactivated whole-virion coronavirus vaccine, especially antibodies targeting S protein, may increase viral infection of Fc receptor (FcR)-expressing

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Ferroptosis is a novel iron-dependent form of cell death implicated in brain pathology. However, whether arsenite is an inducer of ferroptosis in the neuron remains completely unknown. In this study, the seven-week-old healthy C57BL/6 J male mice were treated with environmental related doses (0.5, 5 and 50 mg/L) of arsenite for 6 months via drinking water, and the ferroptosis-related indicators were further determined. Our results demonstrated for the first time that, arsenite exposure significantly reduced the number of neuron and caused the pathological changes of mitochondria in the cerebral cortex of mice. We further revealed that arsenite induced ferroptotic cell death in neuron by accumulation of reactive oxygen species and lipid peroxidation products, disruption of Fe homeostasis, depletion of glutathione and adenosine triphosphate, inhibition of cysteine/glutamate antiporter, activation of mitogen-activated protein kinases and mitochondrial voltage-dependent anion channels pathways, up-regulation of endoplasmic reticulum stress, all of which were involved in the process of ferroptosis. These findings were also verified in the cultured PC-12 cells by using ferropotosis inhibitor, desferoxamine. Taken together, our results not only reveal a novel mechanism that chronic arsenite exposure may trigger the new form of cell death, ferroptosis, but also shed a new light on a potential clue for the intervention and prevention against arsenite-related neurodegenerative diseases.