Neutrophil extracellular traps promote glomerular endothelial injury in IgA nephropathy via the cGAS-STING pathway.

IgA nephropathy (IgAN), a common primary glomerulonephritis, has an incompletely elucidated pathogenesis. Neutrophil extracellular traps (NETs), key components of innate immunity, are known to mediate renal injury in various kidney diseases, yet their role in IgAN remains unclear. In this study, we observed significantly elevated NETs levels in the serum and renal tissues of IgAN patients and mouse models, and DNase I-mediated NETs degradation attenuated glomerular injury in IgAN mice. In vitro, NETs induced injury and glycocalyx shedding in human renal glomerular endothelial cells (HRGECs), accompanied by cGAS-STING pathway activation and upregulation of downstream inflammatory factors. These effects were substantially reversed by DNase I, cGAS/STING inhibitors (RU.521/H151), or siRNA-mediated knockdown of cGAS/STING. Our findings reveal that NETs promote glomerular endothelial injury via the cGAS-STING pathway, offering a potential therapeutic strategy for IgAN.