ArticleJournal of hepatology2025
Bile acids engage the SIPR-STAT3 signaling axis to modulate regulatory T cell responses in fibrosing cholangiopathies.
Article in Journal of hepatology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- [Research advances in autoimmune liver disease in 2025: toward precision regulation and personalized treatment].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2026Article
- Crosstalk between gut microbiota-associated metabolites and adaptive immunity in cholecystitis: a conceptual mechanistic framework and potential therapeutic implications.Frontiers in microbiology · 2026Review
- Mechanisms of T cell activation: Integrating signaling pathways, experimental models, and therapeutic implications.EXCLI journal · 2026Review
- Ubiquitin D Correlates with Disease Severity and T Cell Infiltration in Cholestasis: Evidence from Integrated Bioinformatics and Experimental Analyses.International journal of medical sciences · 2026Article
- Molecular mechanisms underlying T cell subset imbalance and precision therapeutic targets in primary biliary cholangitis.Frontiers in pharmacology · 2026Review
- Sphingolipid Metabolism in the Pathogenesis of Hashimoto's Thyroiditis.International journal of molecular sciences · 2025Review
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Authors and funding
26 authors.
Funding
Abstract
BACKGROUND &
aimsRegulatory T cells (Tregs), a subset of CD4 lymphocytes, protect against inflammatory tissue injury. However, it is currently unknown how retention of bile acids (BA) in fibrosing cholangiopathies like biliary atresia or PSC shape hepatic Treg responses.
methodsTo induce sclerosing cholangitis (SC), mice were fed a diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine for 14 days, followed by 28 days on regular chow to assess tissue repair. Serial hepatic cell and nuclear preparations were subjected to single-cell RNA sequencing and ATAC-seq to define gene regulatory networks controlling Tregs under cholestatic conditions. Candidate molecules mediating the effects of tauro- and chenodeoxycholic acid (T/CDCA) on Tregs were validated in vitro, across three murine models of SC, and in liver tissue samples from 130 infants with biliary atresia.
resultsSingle-cell analyses revealed that Tregs acquired a Th17-like transcriptional program during cholestasis and upregulated amphiregulin (Areg) during the repair phase. S1P receptors were identified as mediators of T/CDCA effects on Tregs, and this was validated both in vitro and in the Abcb4
conclusionBile acids suppress Treg regulatory function by promoting a Th17-like phenotype, thereby limiting their capacity to mitigate immune-mediated cholangiocyte injury. Restoring Treg function and amphiregulin expression may represent a novel therapeutic strategy in fibrosing cholangiopathies. IMPACT AND IMPLICATIONS: In this study, we examined the role of CD4 lymphocytes in controlling bile duct epithelial injury in fibrosing cholangiopathies, with potential implications for developing targeted therapies for BA and PSC. Using single-cell genomics, functional assays, and complementary mouse models of sclerosing cholangitis, we investigated the mechanisms by which chenodeoxycholic acid-derived bile acids determine polarization and suppressor functions of CD4 lymphocytes. Interventions such as reducing hepatic bile acid concentrations with an IBAT (ileal bile acid transporter) inhibitor, antagonizing STAT3 in CD4
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