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Reprogramming Factors Activate a Non-Canonical Oxidative Resilience Pathway That Can Rejuvenate RPEs and Restore Vision

by Chew, Lindsey A , Karg, Margarete M , Cameron, James C , Seifert, Philip , Sinclair, David A , Ksander, Bruce R , Qiu, Xiaojie , Buenrostro, Jason D , Ai, Jiahe , Chen, Zhaoyi , Ei-Brolosy, Mohamed A , Rickman, Catherine Bowes , Shu, Daisy Y , Gregory-Ksander, Meredith , Shen, Han , Tyshkovskiy, Alexander , Tian, Xiao , Saint-Geniez, Magali , Puszynska, Anna M , Gladyshev, Vadim N , Lu, Yuancheng Ryan , Hu, Yan , Lou, Qiannuo , Bell, George W , He, Yue , Shirahama, Shintaro , Zhu, Daniel Y , Jena, Siddhartha G , Zhang, Bohan , Weissman, Jonathan S

in Genetics

2025

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Reprogramming Factors Activate a Non-Canonical Oxidative Resilience Pathway That Can Rejuvenate RPEs and Restore Vision

in Genetics

2025

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Reprogramming Factors Activate a Non-Canonical Oxidative Resilience Pathway That Can Rejuvenate RPEs and Restore Vision

in Genetics

2025

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Journal Article

Reprogramming Factors Activate a Non-Canonical Oxidative Resilience Pathway That Can Rejuvenate RPEs and Restore Vision

Chew, Lindsey A,

Karg, Margarete M,

Cameron, James C,

Seifert, Philip,

Sinclair, David A,

Ksander, Bruce R,

Qiu, Xiaojie,

Buenrostro, Jason D,

Ai, Jiahe,

Chen, Zhaoyi,

Ei-Brolosy, Mohamed A,

Rickman, Catherine Bowes,

Shu, Daisy Y,

Gregory-Ksander, Meredith,

Shen, Han,

Tyshkovskiy, Alexander,

Tian, Xiao,

Saint-Geniez, Magali,

Puszynska, Anna M,

Gladyshev, Vadim N,

Lu, Yuancheng Ryan,

Hu, Yan,

Lou, Qiannuo,

Bell, George W,

He, Yue,

Shirahama, Shintaro,

Zhu, Daniel Y,

Jena, Siddhartha G,

Zhang, Bohan,

Weissman, Jonathan S

2025

Overview

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. OSK-GSTA4 provides a dynamic, Tet2-independent stress-resilience axis.Functional genomics pinpoints GSTA4 as a direct downstream effector activated by OSK.RPE aging involves progressive accumulation of 4-HNE that can be detoxified by GSTA4.Enhancing GSTA4 rejuvenates RPE cells, restores vision and is associated with lifespan-extending interventions.

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Publisher

Cold Spring Harbor Laboratory,Cold Spring Harbor Laboratory Preprints

Subject

Genetics