STING engages PKR to drive lysosomal cell death in lung ischemia-reperfusion injury.

Mitochondrial DNA released during lung ischemia-reperfusion injury activates the cGAS-STING pathway to trigger lysosomal cell death in mouse and rat models. In human lung epithelial cells, STING oligomerization drives autophosphorylation of PKR at serine 33, activating IκB kinase-NF-κB signaling independently of the canonical STING-TBK1 and PKR-eIF2α pathways, which induces LAMP3 transcription and lysosomal membrane permeabilization. Blockade of STING-PKR signaling attenuates epithelial lysosomal cell death and lung injury, identifying PKR as a non-canonical STING effector.