Twenty-five percent of the Veterans receiving care from the VA are being treated for diabetes. Consequently, more than half suffer from diabetic retinopathy, which is an incurable disease that can lead to vision loss. The current treatments for diabetic retinopathy are futile to approximately 75% of diabetics with varying stages of this blinding disease. Accordingly, new therapeutics are needed. Our proposed studies ultimately relate to this clinically relevant need. Recently, we discovered STEAP4 (Six-Transmembrane Epithelial Antigen of the Prostate 4) is upregulated in our VA patients that suffer from diabetic retinopathy. This discovery is noteworthy because STEAP4 is a metabolic enzyme that can mediate inflammation, oxidative stress, and iron accumulation, which are intrinsic pathologies of the onset of diabetic retinopathy. Although the function of STEAP4 in the retina is unknown, our preliminary data provides strong evidence that STEAP4 plays a role in iron uptake and ROS production in the diabetic retina. We will further investigate the mechanistic details of STEAP4’s impact on these pathologies. Since ROS and iron accumulation are inherent to the development of diabetic retinopathy, we will also examine the effect STEAP4 has on ferroptosis, neuroretina damage, visual function, and vascular impairment. These proposed studies will provide a full understanding of the functional impact STEAP4 has on the onset and progression of non-proliferative diabetic retinopathy. Subsequently, we will also examine the intrinsic pathologies of proliferative diabetic retinopathy. Cancer studies provide strong evidence that IL-17A mediates STEAP4 to induce vascularization. We previously determined that IL-17A induces retinal neovascularization, and postulate that STEAP4 is the mediated effector of this vascular proliferation in the retina. To further evaluate this hypothesis, we will examine the unprecedented role of STEAP4 in retinal neovascularization. Our findings could identify a deduced mechanism of vision loss in proliferative diabetic retinopathy. Overall, we are optimistic that all of our proposed work will improve our understanding of this retinal microvascular disease, while identifying a new drug target for diabetic retinopathy.