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ResearchIn-Press PreviewHepatologyImmunologyInflammation Open Access | 10.1172/JCI194879

TET3 is a common epigenetic immunomodulator of pathogenic macrophages

Beibei Liu,1 Yangyang Dai,1 Zixin Wang,1 Jiahui Song,2 Yushu Du,1 Haining Lv,1 Stefania Bellone,1 Yang-Hartwich Yang,1 Andrew Kennedy,3 Songying Zhang,4 Muthukumaran Venkatachalapathy,5 Yulia V. Surovtseva,6 Penghua Wang,7 Gordon G. Carmichael,8 Hugh S. Taylor,1 Xuchen Zhang,9 Da Li,1 and Yingqun Huang1

1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Center of Reproductive Medicine, National Health Commission Key Laboratory , Shengjing Hospital of China Medical University, Shenyang, China

3University of Virginia, Charlottesville, United States of America

4Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

5Department of Chemistry, Yale University, New Haven, United States of America

6Yale Center for Molecular Discovery, Wester Haven, United States of America

7Department of Immunology, University of Connecticut Health Center, Farmington, United States of America

8Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United States of America

9Department of Pathology, Yale University School of Medicine, New Haven, United States of America

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1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Center of Reproductive Medicine, National Health Commission Key Laboratory , Shengjing Hospital of China Medical University, Shenyang, China

3University of Virginia, Charlottesville, United States of America

4Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

5Department of Chemistry, Yale University, New Haven, United States of America

6Yale Center for Molecular Discovery, Wester Haven, United States of America

7Department of Immunology, University of Connecticut Health Center, Farmington, United States of America

8Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United States of America

9Department of Pathology, Yale University School of Medicine, New Haven, United States of America

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1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Center of Reproductive Medicine, National Health Commission Key Laboratory , Shengjing Hospital of China Medical University, Shenyang, China

3University of Virginia, Charlottesville, United States of America

4Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

5Department of Chemistry, Yale University, New Haven, United States of America

6Yale Center for Molecular Discovery, Wester Haven, United States of America

7Department of Immunology, University of Connecticut Health Center, Farmington, United States of America

8Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United States of America

9Department of Pathology, Yale University School of Medicine, New Haven, United States of America

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1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Center of Reproductive Medicine, National Health Commission Key Laboratory , Shengjing Hospital of China Medical University, Shenyang, China

3University of Virginia, Charlottesville, United States of America

4Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

5Department of Chemistry, Yale University, New Haven, United States of America

6Yale Center for Molecular Discovery, Wester Haven, United States of America

7Department of Immunology, University of Connecticut Health Center, Farmington, United States of America

8Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United States of America

9Department of Pathology, Yale University School of Medicine, New Haven, United States of America

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1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Center of Reproductive Medicine, National Health Commission Key Laboratory , Shengjing Hospital of China Medical University, Shenyang, China

3University of Virginia, Charlottesville, United States of America

4Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

5Department of Chemistry, Yale University, New Haven, United States of America

6Yale Center for Molecular Discovery, Wester Haven, United States of America

7Department of Immunology, University of Connecticut Health Center, Farmington, United States of America

8Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United States of America

9Department of Pathology, Yale University School of Medicine, New Haven, United States of America

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1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Center of Reproductive Medicine, National Health Commission Key Laboratory , Shengjing Hospital of China Medical University, Shenyang, China

3University of Virginia, Charlottesville, United States of America

4Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

5Department of Chemistry, Yale University, New Haven, United States of America

6Yale Center for Molecular Discovery, Wester Haven, United States of America

7Department of Immunology, University of Connecticut Health Center, Farmington, United States of America

8Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United States of America

9Department of Pathology, Yale University School of Medicine, New Haven, United States of America

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1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Center of Reproductive Medicine, National Health Commission Key Laboratory , Shengjing Hospital of China Medical University, Shenyang, China

3University of Virginia, Charlottesville, United States of America

4Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

5Department of Chemistry, Yale University, New Haven, United States of America

6Yale Center for Molecular Discovery, Wester Haven, United States of America

7Department of Immunology, University of Connecticut Health Center, Farmington, United States of America

8Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United States of America

9Department of Pathology, Yale University School of Medicine, New Haven, United States of America

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1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Center of Reproductive Medicine, National Health Commission Key Laboratory , Shengjing Hospital of China Medical University, Shenyang, China

3University of Virginia, Charlottesville, United States of America

4Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

5Department of Chemistry, Yale University, New Haven, United States of America

6Yale Center for Molecular Discovery, Wester Haven, United States of America

7Department of Immunology, University of Connecticut Health Center, Farmington, United States of America

8Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United States of America

9Department of Pathology, Yale University School of Medicine, New Haven, United States of America

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1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Center of Reproductive Medicine, National Health Commission Key Laboratory , Shengjing Hospital of China Medical University, Shenyang, China

3University of Virginia, Charlottesville, United States of America

4Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

5Department of Chemistry, Yale University, New Haven, United States of America

6Yale Center for Molecular Discovery, Wester Haven, United States of America

7Department of Immunology, University of Connecticut Health Center, Farmington, United States of America

8Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United States of America

9Department of Pathology, Yale University School of Medicine, New Haven, United States of America

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1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Center of Reproductive Medicine, National Health Commission Key Laboratory , Shengjing Hospital of China Medical University, Shenyang, China

3University of Virginia, Charlottesville, United States of America

4Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

5Department of Chemistry, Yale University, New Haven, United States of America

6Yale Center for Molecular Discovery, Wester Haven, United States of America

7Department of Immunology, University of Connecticut Health Center, Farmington, United States of America

8Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United States of America

9Department of Pathology, Yale University School of Medicine, New Haven, United States of America

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1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Center of Reproductive Medicine, National Health Commission Key Laboratory , Shengjing Hospital of China Medical University, Shenyang, China

3University of Virginia, Charlottesville, United States of America

4Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

5Department of Chemistry, Yale University, New Haven, United States of America

6Yale Center for Molecular Discovery, Wester Haven, United States of America

7Department of Immunology, University of Connecticut Health Center, Farmington, United States of America

8Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United States of America

9Department of Pathology, Yale University School of Medicine, New Haven, United States of America

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1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Center of Reproductive Medicine, National Health Commission Key Laboratory , Shengjing Hospital of China Medical University, Shenyang, China

3University of Virginia, Charlottesville, United States of America

4Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

5Department of Chemistry, Yale University, New Haven, United States of America

6Yale Center for Molecular Discovery, Wester Haven, United States of America

7Department of Immunology, University of Connecticut Health Center, Farmington, United States of America

8Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United States of America

9Department of Pathology, Yale University School of Medicine, New Haven, United States of America

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1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Center of Reproductive Medicine, National Health Commission Key Laboratory , Shengjing Hospital of China Medical University, Shenyang, China

3University of Virginia, Charlottesville, United States of America

4Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

5Department of Chemistry, Yale University, New Haven, United States of America

6Yale Center for Molecular Discovery, Wester Haven, United States of America

7Department of Immunology, University of Connecticut Health Center, Farmington, United States of America

8Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United States of America

9Department of Pathology, Yale University School of Medicine, New Haven, United States of America

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1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Center of Reproductive Medicine, National Health Commission Key Laboratory , Shengjing Hospital of China Medical University, Shenyang, China

3University of Virginia, Charlottesville, United States of America

4Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

5Department of Chemistry, Yale University, New Haven, United States of America

6Yale Center for Molecular Discovery, Wester Haven, United States of America

7Department of Immunology, University of Connecticut Health Center, Farmington, United States of America

8Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United States of America

9Department of Pathology, Yale University School of Medicine, New Haven, United States of America

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1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Center of Reproductive Medicine, National Health Commission Key Laboratory , Shengjing Hospital of China Medical University, Shenyang, China

3University of Virginia, Charlottesville, United States of America

4Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

5Department of Chemistry, Yale University, New Haven, United States of America

6Yale Center for Molecular Discovery, Wester Haven, United States of America

7Department of Immunology, University of Connecticut Health Center, Farmington, United States of America

8Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United States of America

9Department of Pathology, Yale University School of Medicine, New Haven, United States of America

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1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Center of Reproductive Medicine, National Health Commission Key Laboratory , Shengjing Hospital of China Medical University, Shenyang, China

3University of Virginia, Charlottesville, United States of America

4Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

5Department of Chemistry, Yale University, New Haven, United States of America

6Yale Center for Molecular Discovery, Wester Haven, United States of America

7Department of Immunology, University of Connecticut Health Center, Farmington, United States of America

8Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United States of America

9Department of Pathology, Yale University School of Medicine, New Haven, United States of America

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1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Center of Reproductive Medicine, National Health Commission Key Laboratory , Shengjing Hospital of China Medical University, Shenyang, China

3University of Virginia, Charlottesville, United States of America

4Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

5Department of Chemistry, Yale University, New Haven, United States of America

6Yale Center for Molecular Discovery, Wester Haven, United States of America

7Department of Immunology, University of Connecticut Health Center, Farmington, United States of America

8Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United States of America

9Department of Pathology, Yale University School of Medicine, New Haven, United States of America

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1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Center of Reproductive Medicine, National Health Commission Key Laboratory , Shengjing Hospital of China Medical University, Shenyang, China

3University of Virginia, Charlottesville, United States of America

4Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

5Department of Chemistry, Yale University, New Haven, United States of America

6Yale Center for Molecular Discovery, Wester Haven, United States of America

7Department of Immunology, University of Connecticut Health Center, Farmington, United States of America

8Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United States of America

9Department of Pathology, Yale University School of Medicine, New Haven, United States of America

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Published August 12, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI194879.
Copyright © 2025, Liu 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 August 12, 2025 - Version history
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Abstract

Through a combination of single-cell/single-nucleus RNA-sequencing (sc/snRNA-seq) data analysis, immunohistochemistry, and primary macrophage studies, we have identified pathogenic macrophages characterized by TET3 overexpression (Toe-Macs) in three major human diseases associated with chronic inflammation: metabolic dysfunction-associated steatohepatitis (MASH), non-small cell lung cancer (NSCLC), and endometriosis. These macrophages are induced by common factors present in the disease microenvironment (DME). Crucially, the universal reliance on TET3 overexpression among these macrophages enables their selective elimination as a single population, irrespective of heterogeneity in other molecular markers. In mice, depleting these macrophages via myeloid-specific Tet3 knockout markedly mitigates disease progression and the therapeutic effects are recapitulated pharmacologically using a TET3-specific small molecule degrader. Through an unexpected mode of action, TET3 epigenetically regulates expression of multiple genes key to the generation and maintenance of an inflammatory/immunosuppressive DME. We propose that Toe-Macs are a unifying feature of pathogenic macrophages that could be therapeutically targeted to treat MASH, NSCLC, endometriosis, and potentially other chronic inflammatory diseases.

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  • Version 1 (August 12, 2025): In-Press Preview
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