Targeted Intracellular Metal Modulation Attenuates Oxidative Stress and Preserves Retinal Integrity and Function in a Zebrafish Model of Mitochondrial Dysfunction and Age-Related Retinal Degeneration.

Retinal degeneration is associated with mitochondrial dysfunction, oxidative stress, and disruption of metal homeostasis within the retinal pigment epithelium (RPE). Dysregulation of redox-active metals has been implicated in age-related macular degeneration (AMD), but whether targeted intracellular metal modulation preserves retinal structure and function remains incompletely understood. This study explores the effect of metal ion modulation on retinal structure and visual function. Telomir-Zn, a Zinc-based intracellular metal modulator, depletes labile Fe2+, potently inhibits multiple JmjC KDMs, and induces epigenetic reprogramming. In a zebrafish model combining impaired DNA repair with accelerated mitochondrial oxidative stress and progressive retinal degeneration (Sen57^wrn-/-^ND6^-/+^), Telomir-Zn reduced oxidative stress, preserved retinal architecture, improved visual behaviors, and partially normalized telomeric content and CpG methylation patterns. Complementary studies in human ARPE-19 RPE cells showed attenuation of iron/copper-induced ROS and calcium dysregulation, with reciprocal zinc accumulation and labile Fe2+ depletion. These findings suggest that targeted metal modulation and multi-KDM inhibition may be a novel strategy to mitigate oxidative-epigenetic stress to preserve retinal structure/function in degenerative disease, supporting further investigation and development for AMD.