Pannexin1 promotes cellular senescence by triggering mtDNA release to activate the cGAS-STING pathway

Cellular senescence is a pivotal driver of the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). We previously identified Pannexin 1 (Panx1) as an endoplasmic reticulum (ER)-resident calcium (Ca²⁺) leak channel that promotes renal tubular senescence; however, the precise downstream effectors remain elusive. Here, we establish a novel mechanistic link between Panx1 and the cGAS-STING pathway. We show that Panx1 triggers cGAS-STING activation by facilitating the cytosolic release of mitochondrial DNA (mtDNA). Mechanistically, we establish a strict hierarchical relationship in this process: the opening of the mitochondrial permeability transition pore (mPTP) serves as a mandatory prerequisite for BAX translocation to mitochondria, which together orchestrate the efflux of immunogenic mtDNA. Cytosolic mtDNA accumulation engages the cGAS-STING pathway, driving the senescence-associated secretory phenotype (SASP) through NF-κB signaling while concurrently activating IRF3-mediated interferon responses. Genetic or pharmacological blockade of the Panx1-mPTP-BAX-cGAS signaling cascade effectively attenuates the senescent phenotype in human tubular epithelial cells. In mouse models of renal ischemia/reperfusion injury, pharmacological inhibition of Panx1 or STING alleviates renal tubular senescence, fibrosis, and the pathological progression from AKI to CKD. Our findings define the Panx1/mPTP/BAX/cGAS-STING axis as a fundamental driver of cellular senescence, offering refined therapeutic targets for mitigating senescence-associated kidney pathologies.