Targeting the chromatin remodeler BAZ2B mitigates hepatic senescence and MASH fibrosis

Abstract

With increased age, the liver becomes more vulnerable to metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. Deciphering the complex interplay between aging, the emergence of senescent cells in the liver and MASH fibrosis is critical for developing treatments. Here we report an epigenetic mechanism that links liver aging to MASH fibrosis. We find that upregulation of the chromatin remodeler BAZ2B in a subpopulation of hepatocytes (HEPs) is linked to MASH pathology in patients. Genetic ablation or hepatocyte-specific knockdown of Baz2b in mice attenuates HEP senescence and MASH fibrosis by preserving peroxisome proliferator-activated receptor α (PPARα)-mediated lipid metabolism, which was impaired in both naturally aged and MASH mouse livers. Mechanistically, Baz2b downregulates the expression of genes related to the PPARα signaling pathway by directly binding their promoter regions and reducing chromatin accessibility. Thus, our study unravels the BAZ2B-PPARα-lipid metabolism axis as a link from liver aging to MASH fibrosis, suggesting that BAZ2B is a potential therapeutic target for HEP senescence and fibrosis.