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Background: With the increasing prevalence of diabetes in recent years, diabetic nephropathy (DN) has also become a dangerous disease that greatly endangers human health. The study was designed to determine the mechanism and effect of Electro-acupuncture (EA) in alleviating DN-induced inflammation. Methods: Mice were intraperitoneally injected with STZ (streptozotocin, 50 mg/kg, S0130, Sigma, St. Louis, MO, USA) for five consecutive days. After 12 weeks of induction, blood glucose levels were measured (>300 mg/dL). Results: The serum levels of IL-1β and IL-6 were decreased in EA-treated DN mice, and EA protected renal injury. EA could suppress HMGB1/NLRP3/NF-ΚB pathway. HMGB1 inhibition increased the anti-inflammatory effects of EA on DN by suppressing NLRP3/NF-ΚB pathway. The activation of HMGB1 attenuated the anti-inflammatory effects of EA on DN by inducing NLRP3/ NF-ΚB pathway. Conclusion: These results suggested that EA protected DN-induced inflammation through the suppression of NLRP3 inflammasome.