GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE304nnn/GSE304037/primaryOK200GenomicsMus musculusGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE304037GEOGSEfalseReprogramming Factors Activate a Non-Canonical Oxidative Resilience Pathway that Can Rejuvenate RPEs and Restore Vision [GSTA4_ATAC-seq]Oct4, Sox2, and Klf4 (OSK) Yamanaka factors induce pluripotency and reverse age-related epigenetic changes, yet the mechanisms by which they promote rejuvenation remain poorly explored. Oxidative stress contributes to CNS aging and retinal pigmented epithelium (RPE) degeneration in age-related macular degeneration. We find that OSK expression in RPE restores retinal structure and visual function in aged mice and promotes oxidative resilience through a non-canonical, Tet2-independent pathway. Integrative functional genomics identifies GSTA4, a detoxifying enzyme that clears the lipid peroxidation byproduct 4-HNE, as a necessary and sufficient OSK effector. Dynamic GSTA4 regulation by OSK recapitulates a stem cell derived stress resilience program. GSTA4 overexpression alone enhances mitochondrial resilience, rejuvenates the aged RPE transcriptome, and reverses visual decline. GSTA4 is consistently upregulated across diverse lifespan-extending interventions suggesting a broader pro-longevity role. These findings uncover a previously unrecognized protective axis driven by Yamanaka factors that circumvents reprogramming, providing therapeutic insights for age-related diseases.2026/06/11GSE304037GSM9141454GSM9141432GSM9141453GSM9141456GSM9141434GSM9141433GSM9141455GSM9141450GSM9141472GSM9141471GSM9141452GSM9141473GSM9141451GSM9141470GSM9141469GSM9141447GSM9141468GSM9141446GSM9141449GSM9141448GSM9141465GSM9141443GSM9141442GSM9141464GSM9141445GSM9141467GSM9141466GSM9141444GSM9141461GSM9141460GSM9141463GSM9141441GSM9141462GSM9141440GSM9141439GSM9141436GSM9141458GSM9141457GSM9141435GSM9141438GSM9141459GSM914143724247304037Mus musculus