Longevity & AgingSTING Activates a New Necroptosis Pathway That Drives Inflammatory Skin Disease
Researchers at the University of Cologne discovered that STING, the innate immune DNA sensor, can trigger a lethal inflammatory cell death program called necroptosis through ZBP1 — entirely independently of the previously known TNFR1 and FADD death receptor pathways. Using caspase-8-deficient mice and cells, they showed that DNA accumulation activates STING, which upregulates ZBP1 and MLKL, forming a novel ZBP1–RIPK1–RIPK3 complex that executes necroptosis. This pathway was confirmed to drive pathology in SAVI, a rare human interferonopathy caused by gain-of-function STING mutations, and blocking RIPK3 rescued disease in the preclinical SAVI mouse model. The findings identify STING-driven ZBP1-mediated necroptosis as a central disease mechanism and a promising therapeutic target.
