Calcium oxalate (CaOx) crystals cause oxidative damage and inflammation to renal tubular epithelial cells and promote nephrocalcinosis
however, the underlying mechanisms remain unclear and there are no treatment drugs available. This investigation aimed to elucidate how SIRT6 attenuates calcium oxalate nephrocalcinosis-induced renal inflammation and oxidative injury. SIRT6 is a classical deacetylase that is closely associated with both oxidative stress and inflammation. This study investigated the function of SIRT6 in nephrocalcinosis using cellular and mouse models via hematoxylin and eosin (H&E) staining, immunohistochemistry, PCR, Western blotting, and immunofluorescence. Additionally, chromatin immunoprecipitation, Western blot, and double luciferase reporter gene assays were carried out to elucidate the mechanism by which SIRT6 modulates NRF2 transcription. Furthermore, the effects of SIRT6 on mitochondrial function were assessed by measuring ROS and ATP, as well as by JC-1 staining. It was revealed that the inhibition of SIRT6 can effectively alleviate kidney injury. Furthermore, upregulating SIRT6 expression can markedly reduce the inflammatory cell infiltration in mouse kidneys and HK2 cells. Moreover, treatment of SIRT6 overexpressed mice with a NRF2 inhibitor revealed different degrees of changes in the above phenotypes. Additionally, in vitro experiments indicated that SIRT6 can effectively alleviate oxidative injury by protecting mitochondrial function and enhancing the antioxidant capacity of HK2 cells. In conclusion, The results revealed that SIRT6 regulated NRF2 to ameliorate oxidative injury and inflammation via the NRF2/HO-1 axis. Moreover, the scalability of SIRT6-based therapies or potential off-target effects would be explored further, and the potential value of SIRT6-related activators should also be explored in humanized models. These findings indicate new directions and targets for preventing and treating nephrocalcinosis caused by CaOx deposition.