Stimulator of
interferon genes (
STING) is essential for the
type I interferon response against
DNA pathogens. Recent evidence has indicated that
STING also plays a critical role in various diseases such as systemic lupus erythematous,
nonalcoholic fatty liver disease, and
cancer. However, the exact function and mechanism of
STING in
ischemia/reperfusion (I/R) injury, especially in the intestine, remains unknown. In the current study, we evaluated the contribution of
STING to the intestinal I/R progression. The data indicate a robust
STING activation, specifically in the reperfusion period, with the evidence of
interferon response and NF-κB pathway activation. The intestinal I/R injury and distant organ damage was absent in
STING-/- mice. Mechanically, this detrimental effect relies on excess level of lipid peroxidation, which was proved by the level of
4-hydroxynonenal (4-HNE) and the
malondialdehyde (MDA). Additionally, bone marrow derived macrophage (BMDM) was stimulated with
mtDNA or
STING agonist showed a dose- and time-dependent lipid peroxidation and cell death, which could be reverse by
STING-/- or pretreatment of
lipid peroxidation inhibitor.
Liproxstatin-1 could also ameliorate injury I/R induced multiple-organ damage. Similar results were also identified in the GSE96733 database, which indicated that
STING activation was associated with the disbalance of lipid peroxidation and
antioxidant system. Collectively, our results indicate a novel role for
STING activation in the regulation of lipid peroxidation is closely associated with intestinal I/R injury, and that anti-lipid peroxidation is a unique and effective mechanistic approach for intestinal I/R injury and
STING activation associated damage prevention and treatment.