TET3 is a common epigenetic immunomodulator of pathogenic macrophages
Through a combination of single-cell/single-nucleus RNA-Seq (sc/snRNA-Seq) data analysis, immunohistochemistry, and primary macrophage studies, we have identified pathogenic macrophages characterized by Tet methylcytosine dioxygenase 3 (TET3) overexpression (Toe-Macs) in 3 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 enabled their selective elimination as a single population, irrespective of heterogeneity in other molecular markers. In mice, depleting these macrophages via myeloid-specific Tet3 KO markedly mitigated disease progression, and the therapeutic effects were recapitulated pharmacologically using a TET3-specific small-molecule degrader. Through an unexpected mode of action, TET3 epigenetically regulated the 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.
Authors
- Penghua Wang (ORCID: https://orcid.org/0000-0002-7332-1871)
- Yulia V. Surovtseva (ORCID: https://orcid.org/0000-0001-6079-9246)
- Xuchen Zhang (ORCID: https://orcid.org/0000-0002-1484-4672)
- Gordon Carmichael (ORCID: https://orcid.org/0000-0002-0379-6580)
- Songying Zhang (ORCID: https://orcid.org/0000-0001-8044-6237)
- Yingqun Huang (ORCID: https://orcid.org/0000-0002-0663-8465)
- Stefania Bellone (ORCID: https://orcid.org/0000-0001-5909-5292)
- Yangyang Dai (ORCID: https://orcid.org/0009-0004-7917-9337)
- Hugh S. Taylor (ORCID: https://orcid.org/0000-0003-1720-8310)
- Andrew Kennedy (ORCID: https://orcid.org/0000-0002-7888-2109)
- Da Li (ORCID: https://orcid.org/0000-0002-4895-1185)
- Beibei Liu (ORCID: https://orcid.org/0000-0001-8912-8649)
- Zixin Wang (ORCID: https://orcid.org/0009-0007-7863-0298)
- Jiahui Song (ORCID: https://orcid.org/0000-0002-9331-2139)
- Yingying Du (ORCID: https://orcid.org/0000-0002-5149-4632)
- Haining Lv (ORCID: https://orcid.org/0000-0002-0365-8305)
- Muthukumaran Venkatachalapathy
- Yang-Hartwich Yang
Institutions
- Guangzhou University of Chinese Medicine (CN)
- National Health and Family Planning Commission (CN)
- Sir Run Run Shaw Hospital (CN)
- Yale Cancer Center (US)
- Yale University (US)
- Molecular Discovery (United Kingdom) (GB)
- University of Virginia (US)
- UConn Health (US)
- Zhejiang University (CN)
- Nanjing University (CN)
- China Medical University (CN)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-08-12
- DOI
- https://doi.org/10.1172/jci194879
- Citations
- 4
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- Yale University
- National Natural Science Foundation of China