Redox regulation of PDE6 and cGMP signaling in diabetic retinal neurodegeneration

Diabetic retinal neurodegeneration is increasingly recognized as an early and critical component of diabetic retinopathy, driven in part by persistent oxidative stress and dysregulated intracellular signaling. Among these pathways, cyclic guanosine monophosphate (cGMP) signaling plays a central role in photoreceptor function and survival. Phosphodiesterase 6 (PDE6), the key enzyme responsible for cGMP hydrolysis in photoreceptors, has been extensively studied in inherited retinal disorders; however, its regulation under diabetic and redox-imbalanced conditions remains insufficiently defined. In this review, we examine the emerging role of redox imbalance in modulating PDE6 activity and stability in the diabetic retina. We discuss how mitochondrial and non-mitochondrial sources of reactive oxygen species (ROS) may disrupt PDE6 through proteostasis-related mechanisms involving AIPL1-dependent maturation and FAT10-mediated degradation. These alterations may lead to cGMP dysregulation, impaired ion channel activity, calcium imbalance, and photoreceptor dysfunction. We propose that PDE6-cGMP signaling represents a redox-sensitive hub linking oxidative stress to early neuronal damage in diabetic retinopathy. This mechanistic framework highlights PDE6 as a potential molecular target and supports the development of redox-based strategies aimed at preserving retinal function and preventing neurodegeneration.