CIRCAFF3 MODULATION OF P53–ID2 SIGNALING IN MÜLLER GLIA ASSOCIATED WITH INFLAMMATION AND CELL DEATH IN DRY AGE-RELATED MACULAR DEGENERATION

Age-related macular degeneration (AMD) is a progressive retinal neurodegenerative disease and a primary cause of irreversible vision loss in individuals aged 60 years and older. In AMD retinas, Müller glia play a critical role in maintaining retinal homeostasis and undergo activation and remodeling at sites of retinal lesions, including retinal pigment epithelium (RPE) atrophy and choroidal neovascularization (CNV). Müller glia dysregulation contributes to inflammatory and degenerative processes associated with dry AMD. Circular RNAs (circRNAs) have emerged as important regulators in various diseases; however, their role in retinal neurodegenerative disorders remains poorly characterized. To fill this gap, we investigated circRNAs associated with dry AMD pathogenesis using a laser-induced CNV model. CircAff3 levels were downregulated in retinal tissues at day 3 after laser injury. Functional analyses revealed that silencing circAFF3 induced inflammatory responses in both the human Müller glial cell line MIO-M1 and the human retinal pigment epithelial cell line ARPE-19. To further elucidate the role of circAFF3 in retinal degeneration, a transcriptomic profiling of circAFF3-depleted MIO-M1 cells was conducted. These analyses showed that genes downregulated by circAFF3 knockdown in MIO-M1 cells were significantly associated with retinal degeneration. Mechanistically, reduced circAFF3 expression decreased ID2 levels, leading to increased oxidative stress and cell death. Furthermore, our study demonstrated that circAFF3 directly interacts with p53, thereby regulating ID2 expression in MIO-M1 cells. Collectively, these findings suggest that circAFF3 plays a crucial role in Müller glia and RPE dysfunction in dry AMD.