Therapeutic effects of selective p300 histone acetyl-transferase inhibitor on liver fibrosis

Liver fibrosis is caused by chronic liver damage and results in the aberrant accumulation of extracellular matrix during disease progression. Despite the identification of the HAT enzyme p300 as a major factor for liver fibrosis, the development of therapeutic agents targeting the regulation of p300 has not been reported. We validated a novel p300 inhibitor (A6) on the improvement of liver fibrosis using two mouse models, mice on a choline-deficient high-fat diet and thioacetamide-treated mice. We demonstrated that pathological hall-marks of liver fibrosis were significantly diminished by A6 treatment through Masson's trichrome and Sirius red staining on liver tissue and found that A6 treatment reduced the expression of matricellular protein genes. We further showed that A6 treatment improved liver fibrosis by reducing the stability of p300 protein via disruption of p300 binding to AKT. Our findings suggest that targeting p300 through the specific inhibitor A6 has potential as a major therapeutic avenue for treating liver fibrosis. [BMB Reports 2023; 56(2): 114-119]

Automated summary

Liver fibrosis is a result of chronic liver damage and the abnormal accumulation of extracellular matrix. A novel p300 inhibitor (A6) was validated to improve liver fibrosis in two mouse models. A6 treatment significantly reduced pathological hallmarks of liver fibrosis and gene expression of matricellular proteins. Further studies showed that A6 treatment improved liver fibrosis by destabilizing p300 protein through disruption of p300 binding to AKT. Targeting p300 with A6 has potential as a major therapeutic avenue for treating liver fibrosis.