AbstractDiabetic nephropathy is a microvascular complication of diabetes mellitus, threatening the health of millions of people. Herein, we explored a blood glucose independent function of coptisine on diabetic nephropathy. A diabetic rat model was established by intraperitoneal administration of streptozotocin (65 mg/kg). Coptisine treatment (50 mg/kg/day) retarded body weight loss and reduced blood glucose. On the other hand, coptisine treatment also decreased kidney weight and the levels of urinary albumin, serum creatinine, and blood urea nitrogen, indicating an improvement of renal function. Treatment with coptisine also mitigated renal fibrosis, with alleviative collagen deposition. Likewise,in vitrostudy showed that coptisine treatment decreased apoptosis and fibrosis markers in HK-2 cells treated with high glucose. Furthermore, after coptisine treatment, the activation of NOD-like receptor pyrin domain containing protein 3 (NRLP3) inflammasome was repressed, with decreased levels of NLRP3, cleaved caspase-1, interleukin (IL)-1β, and IL-18, indicating that the repression of NRLP3 inflammasome contributed to the effect of coptisine on diabetic nephropathy. In conclusion, this study revealed that coptisine mitigates diabetic nephropathy via repressing the NRLP3 inflammasome. It is indicated that coptisine may have the potential to be used in the diabetic nephropathy treatment.