Decoupling oxidative resilience from reprogramming to rejuvenate the RPE and restore vision [GSTA4_RNA-seq_4]

Oxidative stress contributes to retinal pigmented epithelium (RPE) degeneration in age-related macular degeneration. Here, we show that OSK expression in RPE promotes Tet2-independent oxidative resilience through acute, memory-free transcriptomic changes, and restores visual function in aged mice.

Integrative functional genomics helped identify GSTA4, a detoxifying enzyme that clears the lipid peroxidation byproduct 4-HNE, as a key OSK downstream effector. OSK directly and dynamically activates GSTA4, recapitulating a stem cell-derived stress resilience program. GSTA4 overexpression alone enhances oxidative resilience, rejuvenates the aged RPE transcriptome, and reverses visual decline while avoiding OSK’s pleiotropic effects.