Authors
Haiyan Liu, Yanhong Su, Danni Chen, Boxiao He, Ning Yuan, Qianhao Wang, Baoyuan Zhang, Zhao Feng, Xiaoran Zhang, Yifan Yao, Lei Lei, Anjun Jiao, Yilei Zhang, Baojun Zhang
Published in
Cell death and differentiation. Aug 15, 2026. Epub Aug 15, 2026.
Abstract
Effector regulatory T (eTreg) cells are indispensable for maintaining peripheral immune tolerance and can also interfere with antitumor immunity. However, how epigenetic modifications regulate eTreg differentiation and peripheral maintenance remains largely unknown. Here, we identify the histone deubiquitinating enzyme Bap1 as a pivotal regulator of eTreg cell fate via its H2A deubiquitination activity. Treg-specific deletion of Bap1 markedly impairs eTreg differentiation and promotes ferroptosis through two phases, culminating in a fatal systemic autoimmune syndrome. In the differentiation phase, Bap1 drives the resting Treg (rTreg)-to-eTreg transition by orchestrating metabolic reprogramming through H2AK119 deubiquitination-mediated activation of Stat5, mTORC1, and OXPHOS signaling pathways. In the maintenance phase, Bap1 protects eTreg from ferroptosis through the GSH-Gpx4 axis and MUFA-mediated lipid metabolism. Yy1 interacts with Bap1 at specific genomic loci to regulates the pathways responsible for eTreg differentiation and resistance to ferroptosis. Finally, acute ablation of Bap1 in Treg cells enhances antitumor immunity by disrupting intratumoral eTreg survival and remodeling the tumor microenvironment. Collectively, our findings identify Bap1 as a key epigenetic-metabolic integrator that governs eTreg cell fate to maintain immune tolerance and restrains antitumor immunity. Schematic overview of the mechanism by which Bap1-mediated deubiquitination determines immune tolerance and anti-tumor immunity by modulating eTreg cell differentiation and ferroptosis. Created with BioRender.com. Created in BioRender. Liu, H. (2026) https://BioRender.com/5f76yo3 .
PMID:
42603824
Bibliographic data and abstract were imported from PubMed on 16 Aug 2026.
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