A peripheral subpopulation of retinal pigment epithelium resists oxidative damage through SERPINE3-mediated Caspase-1 inhibition

Huirong Li; Takerra Johnson-Stephenson; Vincent P. Kunze; Wei Yan; David M. McGaughey; Temesgen D. Fufa; Koray Dogan Kaya; Ashley M. Rasys; Davide Ortolan; Dominik Reichert; Congxiao Zhang; Ruchi Sharma; Lijin Dong; Bin Guan; Brian P. Brooks; Tiansen Li; Wei Li; Wencan Wu; Kapil Bharti; Robert B. Hufnagel

doi:10.1172/JCI191272

¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

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¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

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¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

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¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

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¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

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¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

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¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

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¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

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¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

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¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

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¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

Find articles by Zhang, C. in: PubMed | Google Scholar

¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

Find articles by Sharma, R. in: PubMed | Google Scholar

¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

Find articles by Dong, L. in: PubMed | Google Scholar |

¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

Find articles by Guan, B. in: PubMed | Google Scholar |

¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

Find articles by Brooks, B. in: PubMed | Google Scholar |

¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

Find articles by Li, T. in: PubMed | Google Scholar

¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

Find articles by Li, W. in: PubMed | Google Scholar

¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

Find articles by Wu, W. in: PubMed | Google Scholar

¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

Find articles by Bharti, K. in: PubMed | Google Scholar

¹Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

²Retinal Neurophysiology Section, National Eye Institute, NIH, Bethesda, United States of America

³Sanya Institute, China Agricultural University, Hainan; State Key Laborator, College of Animal Science and Technology, China Agricultural University, Beijing, China

⁴Bioinformatics Group, National Eye Institute, NIH, Bethesda, United States of America

⁵Genetic Engineering Core Facility, National Eye Institute, NIH, Bethesda, United States of America

⁶Retinal Cell Biology and Degeneration, National Eye Institute, NIH, Bethesda, United States of America

⁷Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstructi, Eye Hospital, Wenzhou Medical University, Wenzhou, China

Find articles by Hufnagel, R. in: PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI191272.
Copyright © 2026, Li et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published July 7, 2026 - Version history

Heterogeneous degeneration of the retinal pigment epithelium (RPE) leads to irreversible blindness in diseases associated with macular atrophy. However, the underlying mechanisms of regional RPE degeneration remain poorly understood. To address this gap, this study identifies a peripheral RPE subpopulation through spatial, transcriptomic, and functional analyses, thereby contributing to the understanding of the heterogeneity of degenerative RPE cells. Specifically, omics analyses in human and macaque RPE reveal a peripheral RPE cell population with high SERPINE3 expression, while SERPINE3-GFP knock-in mice show comparable expression patterns. In addition, SMART-seq2 analysis further distinguishes transcriptomic profiles between GFP-positive and GFP-negative RPE cells. Under oxidative stress, SERPINE3 expression increases, and GFP-positive cells exhibit improved survival and reentry into the cell cycle. Notably, genetic studies indicate that SERPINE3 is essential for the oxidative stress resistance of GFP-positive cells. Moreover, loss of SERPINE3 results in regional RPE degeneration and increased microglial accumulation in aged mice. Mechanistically, proteinase screening and co-immunoprecipitation indicate that SERPINE3 targets Caspase-1. Importantly, delivery of SERPINE3 via AAV-Serpine3 partially reduces RPE degeneration in an oxidative damage model. These findings advance the understanding of RPE heterogeneous degeneration and highlight SERPINE3 as a protective factor with therapeutic potential for macular atrophy.

Version 1 (July 7, 2026): In-Press Preview

A peripheral subpopulation of retinal pigment epithelium resists oxidative damage through SERPINE3-mediated Caspase-1 inhibition

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A peripheral subpopulation of retinal pigment epithelium resists oxidative damage through SERPINE3-mediated Caspase-1 inhibition

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