Decoupling oxidative resilience from reprogramming to rejuvenate the RPE and restore vision [GSTA4_ATAC-seq_1]

OCT4, SOX2, and KLF4 (OSK) Yamanaka factors can reverse age-related epigenetic changes, yet alternate mechanisms by which they promote tissue resilience remain poorly understood. 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. GSTA4 is upregulated across diverse lifespan-extending interventions suggesting a broader pro-longevity role. These findings uncover a previously unrecognized protective axis directly regulated by OSK, that can be decoupled from reprogramming, providing a framework for developing more precise rejuvenation therapies.