Stimulator of
interferon genes (
STING) is an important adaptor in cytosolic
DNA-sensing pathways. A recent study found that the deletion of
STING ameliorated
cisplatin-induced
acute kidney injury (AKI), suggesting that
STING could serve as a potential target for AKI
therapy. Up to now, a series of small-molecule
STING inhibitors/antagonists have been identified. However, none of the research was performed to explore the role of human
STING inhibitors in AKI. Here, we investigated the effect of a newly generated covalent antagonist, H151, which targets both human and murine
STING, in
cisplatin-induced AKI. We found that H151 treatment significantly ameliorated
cisplatin-induced kidney injury as shown by the improvement of renal function, kidney morphology, and renal
inflammation. In addition, tubular cell apoptosis and increased renal tubular injury marker
neutrophil gelatinase-associated lipocalin induced by
cisplatin were also effectively attenuated in H151-treated mice. Moreover, the mitochondrial injury caused by
cisplatin was also reversed as evidenced by improved mitochondrial morphology, restored
mitochondrial DNA content, and reversed mitochondrial gene expression. Finally, we observed enhanced
mitochondrial DNA levels in the plasma of patients receiving
platinum-based
chemotherapy compared with healthy controls, which could potentially activate
STING signaling. Taken together, these findings suggested that H151 could be a potential therapeutic agent for treating AKI possibly through inhibiting
STING-mediated
inflammation and mitochondrial injury.NEW & NOTEWORTHY Although various stimulator of
interferon genes (
STING) inhibitors have been identified, no research was performed to investigate the role of human
STING inhibitors in AKI. Here, we evaluated the effect of H151 targeting both human and murine
STING on
cisplatin-induced AKI and observed a protection against renal injury possibly through ameliorating
inflammation and
mitochondrial dysfunction.