This study aimed to evaluate the therapeutic effect of IR-61,a novel mitochondrial heptamethine cyanine dye with antioxidant effects,on diabetes mellitus-induced erectile dysfunction(DMED).Eight-week-old male Sprague-Dawley rats were intraperitoneally injected with streptozotocin(STZ)to induce type 1 diabetes.Eight weeks after STZ injection,all rats were divided into three groups:the control group,DM group,and DM+IR-61 group.In the DM+IR-61 group,the rats were administered IR-61(1.6 mg kg-1)twice a week by intravenous injection.At week 13,erectile function was evaluated by determining the ratio of the maximal intracavernous pressure to mean arterial pressure,and the penises were then harvested for fluorescent imaging,transmission electron microscopy,histological examinations,and Western blot analysis.Whole-body imaging suggested that IR-61 was highly accumulated in the penis after intravenous injection.IR-61 treatment significantly improved the maximal ICP of diabetic rats.Additionally,IR-61 ameliorated diabetes-induced inflammation,apoptosis,and phenotypic transition of corpus cavernosum smooth muscle cells(CCSMCs)in penile tissue.IR-61 also attenuated mitochondrial damage,reduced reactive oxygen species production in the corpus cavernosum and upregulated sirtuin 1(SIRT1),sirtuin3(SIRT3),nuclear factor(erythroid-derived 2)-like 2(Nrf2),and heme oxygenase expression in penile tissue.In conclusion,IR-61 represents a potential therapeutic option for DMED by protecting the mitochondria of CCSMCs,which may be mediated by activation of the SIRT1,SIRT3,and Nrf2 pathways.