Tubular STING drives renal fibrosis via extracellular vesicle-mediated activation of the SMO/GLI-1 pathway.

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) remains a major clinical challenge, with its molecular drivers still not fully defined. Here, we identify a previously unrecognized mechanism in which renal tubular cells secrete extracellular vesicles (EVs) enriched in activated STING during early AKI. Using STING-deficient mice, we demonstrate that loss of STING markedly reduces tubular senescence, maladaptive repair, and subsequent fibrosis following injury. Mechanistically, we show that EVs selectively package and transfer activated STING to interstitial fibroblasts, where EV-STING robustly stimulates the Smoothened (SMO) and the downstream effector glioma-associated oncogene 1 (GLI-1) signaling pathway, promoting fibroblast activation and fibrotic progression. Pharmacologic inhibition of EV secretion (GW4869) or blockade of the SMO-GLI-1 pathway (CPN) significantly attenuates kidney injury, underscoring the functional relevance of this STING-SMO-GLI-1 axis. Our findings reveal that STING exerts its pro-fibrotic effects primarily through EV-mediated intercellular trafficking rather than direct intracellular signaling. This study defines a critical tubular cell-STING-EV-fibroblast communication loop that drives the AKI-to-CKD transition and highlights therapeutic opportunities targeting EV-STING release or SMO-GLI-1 signaling to prevent chronic kidney disease.