Iron Activates cGAS-STING Signaling and Promotes Hepatic Inflammation

Abstract

Iron deposition and chronic inflammation are associated with chronic liver diseases, such as alcoholic liver disease, nonalcoholic fatty liver disease, and chronic hepatitis B and C. However, the relationship between iron deposition and chronic inflammation in these diseases is still unclear. In the current study, we aimed to investigate the effect of iron on chronic inflammation in HepG2 cells and mice liver. We demonstrated that iron treatment enhanced the expression of cGAS, STING, and their downstream targets, including TBK1, IRF-3, and NF-κB in HepG2 cells and mice liver. We also found that treatment of HepG2 cells and mice with ferric ammonium citrate increased the expression of inflammatory cytokines, such as IFN-β. Finally, we found that genes involved in iron metabolism and the STING signaling pathway were up-regulated in liver cancer tissues, and the survival time of patients with high expression of these genes in tumor tissues was significantly shortened. These results suggest that iron overload may promote the progress of the chronic liver disease by activating cGAS-STING-mediated chronic inflammation, which provides a new idea for the development of drugs for the treatment of the chronic liver disease.

Quercetin Alleviates Acrylamide-Induced Liver Injury by Inhibiting Autophagy-Dependent Ferroptosis

“…As we all know, FTH1 is the main iron storage protein, which controls cellular free iron concentration . According to a number of studies, increased cargo receptor of ferritinophagy NCOA4 is responsible for FTH1 degradation during ferritinophagy .…”

“…As we all know, FTH1 is the main iron storage protein, which controls cellular free iron concentration. 51 According to a number of studies, increased cargo receptor of ferritinophagy NCOA4 is responsible for FTH1 degradation during ferritinophagy. 52 In our studies, CQ did not decrease the NCOA4 protein level while QCT obviously did that, though CQ and QCT both increased the FTH1 protein level by inhibiting autophagy.…”

Nanoparticle‐Mediated STING Activation for Cancer Immunotherapy

“…The expression of genes involved in iron metabolism and STING pathway were upregulated, suggesting the participant of Fe 2+ in STING pathway. [ 59 ] In all, varieties of metal ions reveal robust immune function via STING pathway which broadens their huge application potential. The absence and accumulation of metal ions can induce cell damage, which facilitates the ion interference therapy development.…”

Current understanding of the cGAS-STING signaling pathway: Structure, regulatory mechanisms, and related diseases

“…Iron is also able to activate the cGAS-STING signaling pathway to induce inflammation. Expression levels of cGAS, STING, and downstream IRF3 are significantly elevated in the livers of iron-treated mice, a novel mechanism of NASH ( Li et al., 2022a ). Based on the pathogenic mechanisms mentioned above, related drugs have been investigated and applied.…”