FXR and BET signaling orchestrate to protect β cells
. Mechanistically, structure-guided modeling and mutational analyses identified a direct interaction between FXR and the BD2 domain of BRD4, depending on specific lysine acetylation sites. Additionally, inhibition of the BD2 domain of BET combined with FXR activation markedly improved β cell survival in human T1D and T2D models established from human pluripotent stem cell (hPSC)-derived islet-like organoids (HILOs). Collectively, these findings establish a BA-bromodomain axis as a transcriptional interface linking metabolic signaling and chromatin regulation, and highlight FXR-BET targeting as a promising strategy to counter progressive β cell failure in diabetes.
Authors
- Naoki Harada (ORCID: https://orcid.org/0000-0003-3846-388X)
- Eli Ipp (ORCID: https://orcid.org/0000-0003-1588-0146)
- Paul D. Gershon (ORCID: https://orcid.org/0000-0002-4904-9193)
- Eiji YOSHIHARA
- Fritz Cayabyab (ORCID: https://orcid.org/0000-0002-6992-5445)
- Sungsoon Fang (ORCID: https://orcid.org/0000-0003-0201-5567)
- Yeva Mirzakhanyan (ORCID: https://orcid.org/0000-0002-4276-8937)
- Liu Wang (ORCID: https://orcid.org/0000-0001-8252-0170)
- Lin‐Feng Chen (ORCID: https://orcid.org/0000-0003-1809-1580)
- Clarissa Tacto
- Yu Hamba
- David Chen
- Jie Wu
- Kiyoka Kim
- Ameen Shaheen
- Jalan Tipirneni
- Nhi Pham
- Jinhyuk Choi
- Harvey Perez
- Zong Wei
Institutions
- University of Illinois Urbana-Champaign (US)
- University of California, Los Angeles (US)
- Yonsei University (KR)
- University of California, Irvine (US)
- UCLA Medical Center (US)
- Mayo Clinic in Arizona (US)
- Harbor–UCLA Medical Center (US)
- Osaka Metropolitan University (JP)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-04-14
- DOI
- https://doi.org/10.64898/2026.04.10.716420
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Allen Foundation
- Common Fund