Epigenetic regulation in liver fibrosis: Focus on the chromatin accessibility landscape

Liver fibrosis is a key pathological process in the progression of chronic liver disease to cirrhosis and hepatocellular carcinoma, with core features including hepatic stellate cells (HSCs) activation and extracellular matrix (ECM) deposition. Nonetheless, the precise spatiotemporal regulatory mechanisms of its gene expression have not been fully clarified. Interestingly, chromatin accessibility, as a core level of epigenetic regulation, directly determines the expression "switch" of fibrosis-related genes by dynamically altering the chromatin open state, which is closely related to key pathological processes such as HSCs activation, hepatocyte injury, and immune cell infiltration. Chromatin accessibility is coordinately modulated by histone modifications, ATP-dependent chromatin remodelers, CpG methylation, as well as enhancers, super-enhancers, and transcription factors, which together constitute a multilayered epigenetic network. Key regulatory mediators, including histone deacetylases (HDACs), histone acetyltransferase p300 (p300), bromodomain-containing protein 4 (BRD4), DNA methyltransferases (DNMTs), and methyl-CpG-binding protein 2 (MeCP2), have emerged as promising therapeutic candidates. Relevant inhibitors or interventions can inhibit HSCs activation and ECM deposition by reversing abnormal chromatin accessibility. An in-depth study of the regulatory network of chromatin accessibility may provide new perspectives on the pathogenesis of liver fibrosis and lay a theoretical foundation for the development of novel precision-targeted drugs.