Blue Light Induces Retinal Ganglion Cell Damage by Stimulating Drp1-Dependent Mitochondrial Fission and Activating NF-κB/NOX4 Axis

Purpose: This study aimed to investigate the mechanisms of blue light-induced neurotoxicity in retinal ganglion cells (RGCs), focusing on the roles of mitochondrial dynamics and oxidative stress. Methods: The impact of blue light exposure was assessed in vitro and in vivo. Key molecular changes were analyzed, and the effects of pharmacological inhibition of Drp1 and/or NOX4 were evaluated on mitochondrial function and RGC apoptosis. Results: Blue light triggered mitochondrial fission by upregulating Drp1 and downregulating MFN2. This disruption promoted the nuclear translocation and phosphorylation of p65, which subsequently enhanced NOX4 transcription and increased mitochondrial reactive oxygen species (ROS) production. Inhibiting either Drp1 or p65 suppressed NOX4 expression and ROS generation. Furthermore, combined inhibition of Drp1 and NOX4 effectively restored mitochondrial function and reduced RGC apoptosis. Conclusions: Both Drp1 and NOX4 contribute to blue light-induced RGC damage, and our findings highlight the importance of the Drp1/mitochondrial fission/p65/NOX4 signaling axis in this process, leading to oxidative stress. Targeting this signaling axis represents a promising therapeutic strategy for preventing blue light-induced retinal injury.