Inhibition of estrogen receptor alpha stabilizes regulatory T cell function in autoimmune hepatitis
Regulatory T cell (Treg) dysfunction plays a key role in the breakdown of immune tolerance in autoimmune hepatitis (AIH), a severe hepatopathy that often progresses to end-stage liver disease despite immunosuppression. Here we report that upregulation of estrogen receptor-alpha (ERα) alters Treg function and stability in pre-menopausal females with AIH, and that blockade of ERα using a specific antagonist stabilizes Tregs and curbs inflammation in humanized mice with liver injury. These findings implicate aberrant ERα signaling in the sex bias of AIH and support ERα inhibition as a potential therapeutic strategy to re-establish immune tolerance.
Authors
- Jonathon J. Graham (ORCID: https://orcid.org/0000-0003-1637-7024)
- Barbora Gromová (ORCID: https://orcid.org/0000-0001-9613-0237)
- Sizun Jiang (ORCID: https://orcid.org/0000-0001-6149-3142)
- Satya K. Kota (ORCID: https://orcid.org/0000-0002-0201-8234)
- Li Gao (ORCID: https://orcid.org/0000-0001-6470-5905)
- Jessica Cassavaugh (ORCID: https://orcid.org/0000-0001-5902-2552)
- Vilas Patwardhan (ORCID: https://orcid.org/0000-0002-1037-0852)
- Ahmadreza Kalbasi
- Maria Serena Longhi (ORCID: https://orcid.org/0000-0002-4510-1249)
- Graziela Scheuer Gomes (ORCID: https://orcid.org/0000-0001-8363-8381)
- A Wei
- Alan Bonder (ORCID: https://orcid.org/0000-0001-6821-0416)
- William Li (ORCID: https://orcid.org/0009-0008-7650-3639)
- Eva Csizmadia (ORCID: https://orcid.org/0000-0003-1996-0370)
- Cortney Cagle (ORCID: https://orcid.org/0009-0000-5885-1519)
- Lina Zhang (ORCID: https://orcid.org/0000-0002-2018-1756)
- Na Wang (ORCID: https://orcid.org/0000-0001-9552-0524)
- Wei Zhang (ORCID: https://orcid.org/0000-0002-9321-6411)
- Du Hanh Nguyen (ORCID: https://orcid.org/0009-0002-4478-863X)
Institutions
- Tufts University (US)
- Universidade Federal do Rio Grande do Sul (BR)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Universität Hamburg (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Shandong Provincial Hospital (CN)
- Shandong Provincial QianFoShan Hospital (CN)
- Shandong First Medical University (CN)
- Comenius University Bratislava (SK)
Publication Details
- Journal
- JHEP Reports
- Published
- 2025-11-17
- DOI
- https://doi.org/10.1016/j.jhepr.2025.101678
- Primary Topic
- Liver Diseases and Immunity
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Crohn's and Colitis Foundation of America
- Crohn's and Colitis Foundation
- Boehringer Ingelheim Fonds
- Agentúra na Podporu Výskumu a Vývoja
- National Institutes of Health