Dimethyl fumarate alleviate hepatic ischemia-reperfusion injury through suppressing cGAS-STING signaling

Hepatic ischemia-reperfusion (I/R) injury frequently occurs during the perioperative phase of liver surgery. Inappropriate activation of STING signaling can trigger excessive inflammation response to aggravate hepatic I/R injury. Dimethyl fumarate (DMF) is an FDA-approved immunomodulatory drug used to treat multiple sclerosis and psoriasis due to its notable anti-inflammation properties. However, the mechanism and targets of DMF in immunomodulation remain unclear. Here, we found that DMF suppresses cGAS-STING activation induced by HSV-1, hering testis DNA, and mitochondrial DNA in a variety of cells. DMF significantly reduces hepatic I/R injury and inhibits cGAS-STING pathway activation in mice. The alleviating effect of DMF on hepatic I/R injury was negligible in STING-knockout mice. Mechanistically, DMF directly inhibits STING activation via an autophagy-independent pathway, and the immunocoprecipitation experiment showed that DMF inhibited STING recruitment of downstream TBK1 and IRF3. Our study found that DMF protects liver I/R injury by inhibiting the STING pathway and may be a potential target of this disease.