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Lookup NU author(s): Dr Teresa BorrelloORCiD, Dr Hannah Paish, Eleanor Graham, Amy Collins, Dr Sam Higginbotham, Dr Glyn NelsonORCiD, Dr David Bulmer, Dr Lee BorthwickORCiD, Stuart Robinson, Jeremy French, John Moir, Steven White, Colin Wilson, Professor Sanjay PandanaboyanaORCiD, John Hammond, Rodrigo Figueiredo, Professor Fiona OakleyORCiD, Professor Derek MannORCiD, Professor Jelena Mann
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. Chronic liver injury characterized by unresolved hepatitis leads to fibrosis, potentially progressing to cirrhosis and hepatocellular carcinoma. Effective treatments for halting or reversing liver fibrosis are currently lacking. This study investigates the potential of HDAC6 as a therapeutic target in liver fibrosis. We synthesized two selective HDAC6 inhibitors, DR-3 and FDR2, and assessed their effects on hepatic stellate cell (HSC) activation and liver fibrosis using human precision cut liver slices (hPCLS). Molecular docking, deacetylation inhibition assays, and various cellular assays were employed to evaluate the specificity and anti-fibrotic efficacy of these inhibitors. DR-3 and FDR2 demonstrated high selectivity for HDAC6 over HDAC1, significantly inhibiting HSC activation markers and fibrogenic gene expression. Both inhibitors increased acetylation of α-tubulin and suppressed TGF-β1-induced SMAD signaling in HSCs. In human precision cut liver slices (hPCLS), DR-3 and FDR2 reduced fibrogenic protein levels and collagen deposition. The selective inhibition of HDAC6 by DR-3 and FDR2 effectively reduces HSC activation and fibrogenesis in liver models, supporting further investigation of HDAC6 inhibitors as potential anti-fibrotic therapies.
Author(s): Borrello MT, Ruzic D, Paish H, Graham E, Collins AL, Scott R, Higginbotham S, Radovic B, Nelson G, Bulmer D, Borthwick LA, Robinson SM, French J, Moir J, White SA, Wilson C, Pandanaboyana S, Hammond J, Thakkar R, Alrawashdeh W, Figueiredo R, Petkovic M, Nikolic K, Oakley F, Mann DA, Mann J
Publication type: Article
Publication status: Published
Journal: FEBS Journal
Year: 2025
Pages: Epub ahead of print
Online publication date: 14/03/2025
Acceptance date: 28/02/2025
Date deposited: 09/04/2025
ISSN (print): 1742-464X
ISSN (electronic): 1742-4658
Publisher: John Wiley and Sons Inc.
URL: https://doi.org/10.1111/febs.70062
DOI: 10.1111/febs.70062
Data Access Statement: Data related to the synthesis of the HDAC6 small molecule inhibitors (DR-3 and FDR2) and structural characterization are available within the article and the Supporting Information (NMR characterization – Figs S1–S5).
PubMed id: 40084612
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