Histone acetyltransferases and deacetylase 6 (HDAC6) Promotes Hepatic Stellate Cell Activation and Liver Fibrosis.
9 affiliations
- 1MRC-OSTRC, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea.
- 2KNU G-LAMP Project Group, KNU Institute of Basic Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.
- 3Honam Regional Future Drug Development Convergence Education & Research Division (BK21 FOUR), Chosun University, Republic of Korea.
- 4College of Korean Medicine, Dongshin University, Naju, Jeollanam-do, 58245, South Korea.
- 5Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Korea.
- 6School of Pharmacy, Jeonbuk National University, Jeonju, 54896, Republic of Korea.
- 7Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 52727, Republic of Korea.
- 8Central Research Center, Okchundang Inc., Daegu 41059, Republic of Korea.
- 9School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
Abstract
Liver fibrosis results from excessive extracellular matrix (ECM) deposition following chronic hepatocyte injury. Hepatic stellate cell (HSC) activation is central to fibrogenesis; however, the regulatory mechanisms controlling this process remain unclear. Protein acetylation, regulated by histone acetyltransferases and deacetylases (HDACs), modulates gene expression and protein stability. To date, no studies have explored acetylation dynamics during HSC activation using proteomic approaches. In this study, we investigated the role of acetylation in HSC activation and liver fibrosis. Proteomic profiling of primary mouse HSCs was performed to assess global protein acetylation and the expression of HDACs and SIRTs during HSC activation. Activated HSCs exhibited reduced global protein acetylation, increased HDAC2/3/6 expression, and decreased SIRTs expression. Selective inhibition of HDAC6, but not HDAC2/3, suppressed TGF-β-induced HSC activation. TGF-β increased HDAC6 expression via Smad3-dependent transcription, and HDAC6 promoted fibrogenic gene expression through Smad activation. Proteomic screening identified acetyl-CoA acetyltransferase 1 (ACAT1) as a novel HDAC6 substrate; HDAC6 overexpression enhanced ACAT1 binding and reduced its acetylation. In vivo, pharmacological inhibition of HDAC6 lowered ALT and AST levels and improved histological changes in fibrotic mice. Our results suggest that selective HDAC6 inhibition may represent a promising therapeutic strategy for treating liver fibrosis.
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BibTeX
@article{lee2026histone,
title = {{Histone acetyltransferases and deacetylase 6 (HDAC6) Promotes Hepatic Stellate Cell Activation and Liver Fibrosis.}},
author = {Ji Hyun Lee and Ann-Yae Na and Ji Hye Kim and Tae Hyun Park and Ji Hye Yang and Joo Yong Lee and Chang Yeob Han and Sohi Kang and Il Je Cho and Sangkyu Lee and Sung Hwan Ki},
journal = {International journal of biological sciences},
year = {2026},
month = sep,
doi = {10.7150/ijbs.137447},
url = {https://europepmc.org/article/MED/42910219},
note = {CC BY},
}
RIS
TY - JOUR
TI - Histone acetyltransferases and deacetylase 6 (HDAC6) Promotes Hepatic Stellate Cell Activation and Liver Fibrosis.
AU - Ji Hyun Lee
AU - Ann-Yae Na
AU - Ji Hye Kim
AU - Tae Hyun Park
AU - Ji Hye Yang
AU - Joo Yong Lee
AU - Chang Yeob Han
AU - Sohi Kang
AU - Il Je Cho
AU - Sangkyu Lee
AU - Sung Hwan Ki
PY - 2026
DA - 2026/09/10
JO - International journal of biological sciences
DO - 10.7150/ijbs.137447
UR - https://europepmc.org/article/MED/42910219
AB - Liver fibrosis results from excessive extracellular matrix (ECM) deposition following chronic hepatocyte injury. Hepatic stellate cell (HSC) activation is central to fibrogenesis; however, the regulatory mechanisms controlling this process remain unclear. Protein acetylation, regulated by histone acetyltransferases and deacetylases (HDACs), modulates gene expression and protein stability. To date, no studies have explored acetylation dynamics during HSC activation using proteomic approaches. In this study, we investigated the role of acetylation in HSC activation and liver fibrosis. Proteomic profiling of primary mouse HSCs was performed to assess global protein acetylation and the expression of HDACs and SIRTs during HSC activation. Activated HSCs exhibited reduced global protein acetylation, increased HDAC2/3/6 expression, and decreased SIRTs expression. Selective inhibition of HDAC6, but not HDAC2/3, suppressed TGF-β-induced HSC activation. TGF-β increased HDAC6 expression via Smad3-dependent transcription, and HDAC6 promoted fibrogenic gene expression through Smad activation. Proteomic screening identified acetyl-CoA acetyltransferase 1 (ACAT1) as a novel HDAC6 substrate; HDAC6 overexpression enhanced ACAT1 binding and reduced its acetylation. In vivo, pharmacological inhibition of HDAC6 lowered ALT and AST levels and improved histological changes in fibrotic mice. Our results suggest that selective HDAC6 inhibition may represent a promising therapeutic strategy for treating liver fibrosis.
SN - 1449-2288
ER -