Bidirectional Crosstalk Between cGAS-STING and Necroptosis: From Mitochondrial DNA Release to Inflammatory Disease.

The cGAS-STING pathway, a cornerstone of cytosolic DNA sensing, and necroptosis, a pro-inflammatory regulated cell death modality, are increasingly recognized as intimately interconnected axes that profoundly influence disease pathogenesis. This review synthesizes current knowledge on their bidirectional crosstalk, emphasizing the molecular underpinnings and therapeutic implications. We detail how cGAS -STING activation can precipitate necroptosis through type I interferon and TNF-α synergy, as well as transcriptional upregulation of ZBP1, with mitochondrial damage and mtDNA release serving as critical upstream triggers. Reciprocally, in certain necroptotic settings, phosphorylated MLKL can permeabilize mitochondrial membranes to liberate mtDNA, although this is not yet established as an obligatory feature of all MLKL-dependent necroptosis, which activates cGAS-STING independently of plasma membrane rupture, while RIPK3 can drive mitochondrial dysfunction to similar effect. This reciprocal engagement often escalates into a self-amplifying feedback loop that drives chronic inflammation and tissue injury across diverse pathologies, including neurodegenerative disorders, sterile organ injury, and cancer, though it can also be harnessed for antitumor immunity. However, this crosstalk is context-dependent rather than uniformly amplifying: in some settings, STING activation restrains necroptosis, as observed during