Abstract： Background and Purpose: Diabetic peripheral neuropathy (DPN), a common chronic complication in type 1 and type 2 diabetes due to metabolic dysregulation and nerve ischemia, was the focus. This research aimed to explore the therapeutic potential of UFP-101, an NOPR antagonist, in DPN. Experimental Approach: Thirty male Sprague - Dawley rats were divided into five groups: control, DPN model, and three DPN groups treated with different doses of UFP-101 (0.01mg/kg, 0.03mg/kg, 0.1mg/kg). Human umbilical vein endothelial cells were also split into six groups with different treatments related to glucose levels, N/OFQ, UFP-101, and inhibitors. Key Results: High - dose UFP-101 (0.03mg/kg and 0.1mg/kg) had positive effects. It decreased Tail flicking latency, reduced sciatic nerve stimulation thresholds, and restored femoral artery blood flow. Molecularly, it downregulated PKC phosphorylation, decreased MME protein expression, increased serum CNP levels, and improved nerve fiber integrity. In cell culture, Go6976 and LCZ696 reduced MME expression, and UFP - 101, Go6976, and LCZ696 increased CNP levels. Conclusions and Implications: UFP-101 mitigates DPN progression by modulating the PKC - MME - CNP signaling axis, indicating its potential as a targeted DPN treatment.