OBJECTIVE Refractory wound in diabetic patients is a serious complication that often leads to amputation with limited treatment regimens.The present study was designed to determine the protective effect of soy isoflavone genistein on diabetic wound healing and investigate the underlying mechanisms.METHODS Streptozotocin (STZ)-induced type 1 diabetes mice with full-thickness excisional wound were received 0.2, 1 and 5 mg· kg-1 · d-1 of genistein via subcutaneous injection.RESULTS Genistein dose-dependently rescued the delay of wound closure in diabetic mice.5 mg· kg-1 ·d-1 of genistein treatment significantly increased the mean perfusion rate, in vitro genistein protected against high glucose-induced impairment of capillary tube formation in cultured endothelial cells.Under diabetic condition, there is significant increased superoxide anion (O2-) production and decreased nitrite levels in wound tissues.Genistein treatment in all dose range significantly normalized the elevated O2-production and reversed the attenuated nitrite level.In the diabetic wound tissues, the inducible nitric oxide synthase (iNOS) was largely activitied and genistein administration maintained increased iNOS activity.Moreover, genistein attenuated diabetic cutaneous SIRT1 and forkhead box O transcription factor 1 (FoxO1) levels and potentiated ace-FoxO1 in a dose-dependent manner.CONCLUSION Genistein could rescue the delayed wound healing and improved wound angiogenesis in STZ-induced type 1 diabetes mice, at least in part, by suppression of FoxO1, iNOS activity and oxidative stress.