Mitochondrial DNA leakage and micronucleus formation activate the cGAS-STING pathway in aristolochic acid I-induced nephritis.

Aristolochic acid I (AAI), a compound in Aristolochiaceae family of plants, has carcinogenic and nephrotoxic effects. However, medicinal and environmental AAI exposure persists. The genotoxic impacts of AAI are reasonably well understood; however, the mechanisms governing its nephrotoxicity and the underlying interaction between its genotoxicity and nephrotoxic characteristics remain elusive. Here, we uncovered a link between AAI-induced DNA damage and the activation of the cGAS-STING pathway, a previously unidentified participant in nephritis. We hypothesized that AAI-induced oxidative stress and genetic damage trigger the release of mitochondrial and micronuclear DNA, which, in turn, activates the cGAS-STING pathway. This mechanism has been validated separately in animal models at a dosage of 15 mg/kg of AAI and in vitro cultures at the IC50 doses. The findings of the involvement of the cGAS-STING pathway, particularly the participation of micronuclear DNA, not only help to understand the nature of AAI-induced nephrotoxicity but also have broader implications for the study of other genotoxic substances, offering potential strategies for mitigating their detrimental effects.