Novel Perspectives in Hepatic Ischemia-Reperfusion Injury: The cGAS-STING Pathway

In hepatic ischemia-reperfusion injury (HIRI), the cGAS-STING pathway serves as a central regulatory hub by sensing aberrant mitochondrial DNA (mtDNA) release. Ischemia-reperfusion triggers mtDNA leakage through mechanisms including mitochondrial permeability transition pore (mPTP) opening, voltage-dependent anion channel (VDAC) oligomerization, and excessive fission. Cytosolic mtDNA activates cyclic GMP-AMP synthase (cGAS), catalyzing the synthesis of cGAMP, which stimulates stimulator of interferon genes (STING) oligomerization and translocation. This activates the TBK1-IRF3/NF-κB axis, driving expression of type I interferons (IFN-I) and pro-inflammatory cytokines, thereby amplifying neutrophil infiltration, macrophage pyroptosis, and hepatocyte apoptosis. The pathway bidirectionally interacts with oxidative stress and mitophagy, exhibiting cell-type specificity: in hepatocytes, cGAS promotes protective STING-independent autophagy, whereas in macrophages, STING drives inflammatory activation. Targeted inhibition of cGAS-STING signaling and mitochondrial stabilization represent promising therapeutic strategies.