EP300 inhibition alleviates acute-on-chronic liver failure through modulation of scar-associated macrophages

Abstract

Acute-on-chronic liver failure is a severe syndrome with high short-term mortality, and current treatments are limited to liver transplantation and supportive care. Here we show that EP300 inhibition alleviates acute-on-chronic liver failure by targeting scar-associated macrophages, a subset that proliferates during disease progression and whose impaired antibacterial function is linked to poor prognosis. EP300 inhibition enhances the antibacterial activity of scar-associated macrophages through transcriptional repression of ACOD1. ACOD1 expression is induced in scar-associated macrophages during acute-on-chronic liver failure, and its loss mitigates hepatic destruction and prolongs survival in male mice with acute-on-chronic liver failure by enhancing the phagocytic function of scar-associated macrophages. These findings suggest that EP300 inhibition alleviates acute-on-chronic liver failure through ACOD1-dependent reprogramming of scar-associated macrophages, providing a promising therapeutic strategy for acute-on-chronic liver failure.

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BibTeX

@article{chen2026ep300,
  title = {{EP300 inhibition alleviates acute-on-chronic liver failure through modulation of scar-associated macrophages}},
  author = {Panyu Chen and Bingyuan Huang and Wentao Chen and Xiao Lin and Changjie Yang and Chen Wang and Wenxi Su and Zhaokai Zeng and Yunyun Ren and Shijie Fan and Yun Song and Rong Fu and Yixuan Xu and Xiaosong Chen and Xiaogang Xiang and Guangming Li and Kaixian Chen and Xiong Ma and Yugang Wang and Yuanyuan Zhang and Min Shi and Cheng Luo},
  journal = {Nature Communications},
  year = {2026},
  month = oct,
  doi = {10.1038/s41467-026-78245-x},
  url = {https://www.nature.com/articles/s41467-026-78245-x},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - EP300 inhibition alleviates acute-on-chronic liver failure through modulation of scar-associated macrophages
AU  - Panyu Chen
AU  - Bingyuan Huang
AU  - Wentao Chen
AU  - Xiao Lin
AU  - Changjie Yang
AU  - Chen Wang
AU  - Wenxi Su
AU  - Zhaokai Zeng
AU  - Yunyun Ren
AU  - Shijie Fan
AU  - Yun Song
AU  - Rong Fu
AU  - Yixuan Xu
AU  - Xiaosong Chen
AU  - Xiaogang Xiang
AU  - Guangming Li
AU  - Kaixian Chen
AU  - Xiong Ma
AU  - Yugang Wang
AU  - Yuanyuan Zhang
AU  - Min Shi
AU  - Cheng Luo
PY  - 2026
DA  - 2026/10/07
JO  - Nature Communications
DO  - 10.1038/s41467-026-78245-x
UR  - https://www.nature.com/articles/s41467-026-78245-x
AB  - Acute-on-chronic liver failure is a severe syndrome with high short-term mortality, and current treatments are limited to liver transplantation and supportive care. Here we show that EP300 inhibition alleviates acute-on-chronic liver failure by targeting scar-associated macrophages, a subset that proliferates during disease progression and whose impaired antibacterial function is linked to poor prognosis. EP300 inhibition enhances the antibacterial activity of scar-associated macrophages through transcriptional repression of ACOD1. ACOD1 expression is induced in scar-associated macrophages during acute-on-chronic liver failure, and its loss mitigates hepatic destruction and prolongs survival in male mice with acute-on-chronic liver failure by enhancing the phagocytic function of scar-associated macrophages. These findings suggest that EP300 inhibition alleviates acute-on-chronic liver failure through ACOD1-dependent reprogramming of scar-associated macrophages, providing a promising therapeutic strategy for acute-on-chronic liver failure.
SN  - 2041-1723
ER  -

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