Diabetic nephropathy (DN) is one of the most serious complications of diabetes mellitus and the main cause of end-stage renal disease (ESRD). Activation of the NLRP3 inflammasome has been proven to play an important role in the development of DN. Thus, specific and direct targets of NLRP3 inflammasome assembly may have therapeutic potential. CY-09 is a new NLRP3 inflammasome specific inhibitor that has been shown to protect against non-alcoholic fatty liver disease (NAFLD) by inhibiting the activation of the NLRP3 inflammasome. However, its role in kidney disease, especially DN, has not been reported.In this study, we used HE staining to assess renal pathological damage in each group, and RT-PCR, immunofluorescence and WB were performed to detect the expression changes in inflammatory and fibrosis proteins. The apoptosis level was detected by TUNEL staining.Here, we showed increased inflammation, oxidative stress, apoptosis and fibrosis in db/db mice, while CY-09 exerted renoprotection by inhibiting NLRP3 inflammasome activation. In vitro, CY-09 also inhibited NLRP3 and reduced caspase-1, IL-18, IL-1β and apoptosis in a dose-dependent manner.CY-09 effectively protects the kidney from hyperglycemia induced damage by inhibiting the NLRP3 inflammasome and may be a promising therapeutic strategy to prevent the progression of DKD.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.