GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE304nnn/GSE304040/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE304040GEOGSEfalseReprogramming Factors Activate a Non-Canonical Oxidative Resilience Pathway that Can Rejuvenate RPEs and Restore Vision [GSTA4_RNA-seq_3]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.2026/06/11GSE304040GSM9141520GSM9141498GSM9141511GSM9141500GSM9141510GSM9141521GSM9141499GSM9141509GSM9141517GSM9141506GSM9141505GSM9141516GSM9141508GSM9141519GSM9141507GSM9141518GSM9141513GSM9141502GSM9141512GSM9141501GSM9141515GSM9141504GSM9141514GSM914150324247304040Mus musculus