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ResearchIn-Press PreviewCardiologyCell biology Open Access | 10.1172/jci.insight.204132

Perm1 enhances Nrf2-driven antioxidant defense through Keap1 oxidation during myocardial ischemia/reperfusion injury

Shin-ichi Oka,1 Chun-Yang Huang,1 Masato Matsushita,1 Allen Sam Titus,1 Yasuki Nakada,1 Risa Mukai,1 Samta Veera,1 Youssef Mourad,1 Ghassan Yehia,2 Peter Romanienko,2 Yimin Tian,1 Peiyong Zhai,1 and Junichi Sadoshima1

1Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, United States of America

2Genome Editing Shared Resource, Rutgers Cancer Institute, New Brunswick, United States of America

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1Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, United States of America

2Genome Editing Shared Resource, Rutgers Cancer Institute, New Brunswick, United States of America

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1Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, United States of America

2Genome Editing Shared Resource, Rutgers Cancer Institute, New Brunswick, United States of America

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1Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, United States of America

2Genome Editing Shared Resource, Rutgers Cancer Institute, New Brunswick, United States of America

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1Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, United States of America

2Genome Editing Shared Resource, Rutgers Cancer Institute, New Brunswick, United States of America

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1Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, United States of America

2Genome Editing Shared Resource, Rutgers Cancer Institute, New Brunswick, United States of America

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1Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, United States of America

2Genome Editing Shared Resource, Rutgers Cancer Institute, New Brunswick, United States of America

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1Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, United States of America

2Genome Editing Shared Resource, Rutgers Cancer Institute, New Brunswick, United States of America

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1Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, United States of America

2Genome Editing Shared Resource, Rutgers Cancer Institute, New Brunswick, United States of America

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1Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, United States of America

2Genome Editing Shared Resource, Rutgers Cancer Institute, New Brunswick, United States of America

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1Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, United States of America

2Genome Editing Shared Resource, Rutgers Cancer Institute, New Brunswick, United States of America

Find articles by Tian, Y. in: PubMed | Google Scholar

1Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, United States of America

2Genome Editing Shared Resource, Rutgers Cancer Institute, New Brunswick, United States of America

Find articles by Zhai, P. in: PubMed | Google Scholar

1Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, United States of America

2Genome Editing Shared Resource, Rutgers Cancer Institute, New Brunswick, United States of America

Find articles by Sadoshima, J. in: PubMed | Google Scholar |

Published May 12, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.204132.
Copyright © 2026, Oka 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 May 12, 2026 - Version history
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Abstract

Ischemia/reperfusion (IR) enhances oxidative stress, leading to myocardial injury. Although Perm1 promotes cytoprotective mechanisms, the underlying mechanisms are poorly understood. Cysteine oxidation of Keap1 alleviates Cul3-mediated ubiquitination/degradation of Nrf2 and promotes antioxidant transcription. Here we show that Perm1 activates Nrf2 through cysteine oxidation of Keap1 and stabilization of Nrf2. Endogenous Perm1 was downregulated during IR, whereas the rescue of Perm1 reduced IR injury. Downregulation of Perm1 exacerbated oxidative stress, whereas upregulation of Perm1 alleviated it, accompanied by downregulation and upregulation of Nrf2-regulated antioxidant genes, respectively. Perm1 promoted oxidation of cysteine residues in Keap1, possibly through thiol-disulfide exchange reactions, which decreases Keap1-Nrf2 interaction and inhibits Cul3-mediated degradation of Nrf2. We identified Cys121 and Cys746 in Perm1 as critical for Keap1 oxidation and cardioprotection. Thus, Perm1 induces cysteine oxidation of Keap1, thereby conferring myocardial resistance to IR injury by inducing Nrf2 stabilization and transcriptional activation of antioxidant genes.

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