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Background Excessive levels of oxidative stress and long-term inflammatory state seriously affect wound healing in diabetic patients. At present, there are biological agents, traditional Chinese medicines, stem cell therapy etc. used in treating diabetic cutaneous ulcer (DCU) . Due to lack of sufficient evidence of safety and effectiveness, these methods are not widely applied in clinical treatment. Thus new drugs need to be discovered urgently. Hyaluronic acid oligosaccharide (o-HA) is a potential drug for the treatment of DCU because of its antioxidant and anti-inflammatory properties. Objective To observe the effect of o-HA on DCU wound healing and explore its influence on oxidative stress Nrf2 signaling pathway. Methods This experiment was conducted from April to December, 2021. Ninety SPF male mice of six-week-old from Kunming were selected. Ten of them were reserved as the normal control group (NC group) and the rest were injected with streptozotocin (STZ) by abdomen to induce diabetes mouse model. Sixty diabetic mice modeled successfully were divided into 6 groups according to random number table with ten in each group, namely the diabetic model group (DM group) , the recombinant human epidermal growth factor positive control group (rhEGF group) , the blank matrix negative group (matrix group) , low-dose o-HA treatment group (0.5% o-HA group) , medium-dose o-HA treatment group (1% o-HA group) and high-dose o-HA treatment group (2% o-HA group) . The DCU model was established in all mice by way of the full-thickness skin excision ring splint. The wounds in NC and DM group were not treated. For the other groups, the corresponding medicines were evenly applied to and around the wounds after daily disinfection. The mice in rhEGF group were administered once a day while the mice in the 0.5%, 1% and 2% o-HA group were medicated twice a day for consecutive 14 days. The wound healing condition of DCU mice was recorded after being treated on the first, the 7th and the 14th day. The morphological changes of granulation tissue, collagen fiber formation and angiogenesis in mice wounds were observed by HE staining, Masson staining and CD34 immunohistochemical staining. The serum SOD and MDA levels of mice were examined by the kits. The Nrf2, HO-1 and NQO1 protein expression in wound tissue of mice were detected by Western-blotting after the administration of 14 days. Results On the seventh day of administration, the wound healing rate of rhEGF group and 1% o-HA group was higher than that of DM group and the wound healing rate of 0.5% o-HA group and 2% o-HA group was lower than that of NC group and higher than that of DM group. On the 14th day of administration, the wound healing rate of rhEGF group, 0.5% o-HA group, 1% o-HA group and 2% o-HA group was higher than that of DM group (P