Activator protein-1 mediates blue light-induced phototoxicity in retinal pigment epithelial cells

Age-related macular degeneration is a leading cause of vision loss and is characterized by the accumulation of drusen in the retinal pigment epithelium. N-retinylidene-N-retinylethanolamine (A2E), a major component of drusen, induces phototoxicity upon exposure to blue light. Given that blue light activates the MAPK pathway and triggers apoptosis, the present study aimed to determine the role of signaling via the activator protein-1 (AP-1) transcription factor in A2E-laden ARPE-19 cells. RNA-sequencing identified significant upregulation of the UV response and p53 pathways. In silico analysis predicted that JUN was a key upstream transcriptional regulator, and experimental validation confirmed increased JUN phosphorylation and AP-1 target gene expression upon blue light exposure. Furthermore, blue light treatment decreased BCL2 and increased BAX protein levels, thereby promoting apoptosis via caspase activation and PARP cleavage, as also confirmed by flow cytometry. These findings suggest that blue light induces apoptosis via JUN, which activates AP-1 in A2E-laden ARPE-19 cells. The present study provides new insights into the molecular mechanisms underlying blue light-induced retinal damage and its potential contribution to the progression of age-related macular degeneration.