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.