The peptide Ac2–26 preserves mitochondrial function and neuronal survival in human retinal cells and organoids under hyperglycemic and inflammatory stress

Diabetic retinopathy (DR) is a neurodegenerative disease characterized by hyperglycemia-induced inflammation, mitochondrial dysfunction, and progressive neuronal cell death, leading to irreversible vision loss. Retinal ganglion cells (RGCs) are particularly vulnerable to this hostile microenvironment, undergoing apoptosis before microvascular pathology becomes clinically evident. However, therapeutic strategies targeting these early neurodegenerative events remain limited. Here, we investigated the protective effects of the Annexin A1 mimetic peptide Ac 2–26 using complementary human retinal organoid (RO) and organoid-derived retinal ganglion cell (RGC) models of diabetes-like stress. In retinal organoids, Ac 2–26 significantly attenuated high glucose-induced retinal degeneration by coordinately suppressing intrinsic and extrinsic apoptotic pathways, reducing Müller cell gliosis, and selectively modulating inflammatory mediators associated with DR progression. In organoid-derived RGCs, Ac 2–26 reduced mitochondrial oxidative stress, restored mitochondrial bioenergetics, and prevented neuronal apoptosis under both hyperglycemic and inflammatory conditions. Mechanistically, these protective effects were associated with FPR2-dependent suppression of the p38/NOX4 signaling axis, identifying oxidative stress regulation as a central mechanism underlying mitochondrial preservation. Collectively, our findings demonstrate that Ac 2–26 acts as a pro-resolving neuroprotective agent that targets convergent inflammatory and mitochondrial pathways involved in early diabetic retinal degeneration, highlighting the FPR2–p38–NOX4 axis as a promising therapeutic target for early intervention in diabetic retinopathy.