Sustained human C-peptide protects against retinal neurodegeneration via PEDF restoration and oxidative stress inhibition in a mouse model of age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the elderly. The molecular events that initiate retinal degeneration in dry AMD remain incompletely understood, and effective therapeutic options are limited. Here, we investigated the therapeutic potential of K9-C-peptide against sodium iodate (NaIO3)-induced retinal neurodegeneration and explored its underlying molecular mechanisms. K9-C-peptide markedly attenuated NaIO3-induced retinal apoptosis, thinning, and structural disruption. These protective effects were accompanied by significant suppression of ROS generation, decreased expression of pro-inflammatory cytokines, and inhibition of reactive gliosis. Mechanistically, K9-C-peptide restored NaIO3-induced downregulation of pigment epithelium-derived factor (PEDF). Consistently, intravitreal administration of hydrogel-formulated PEDF similarly reduced oxidative stress and retinal degeneration, supporting a central role for PEDF in mediating the protective effects of K9-C-peptide. Both K9-C-peptide and PEDF improved impaired axonal transport, further confirming their neuroprotective efficacy. Notably, sustained intraocular delivery of human C-peptide or PEDF conferred robust protection against NaIO3-induced retinal neurodegeneration for at least three weeks following a single administration. These findings suggest that K9-C-peptide may serve as a long-acting therapeutic candidate that targets early oxidative and inflammatory events, potentially through PEDF restoration, in NaIO3-induced retinal degeneration. This study provides mechanistic insight into the antioxidative and anti-inflammatory actions of C-peptide-based therapy in dry AMD-like pathology.