AbstractBackgroundA fibrotic liver may have an impaired regenerative capacity. Because liver transplantation is donor limited, understanding the regenerative ability of a fibrotic liver is important.MethodsA two‐thirds partial hepatectomy (PH) was performed in C57Bl/6 mice with or without carbon tetrachloride (CCl4) treatment. Liver regeneration in the fibrotic liver after PH was assessed by the intrahepatic expression of the cell cycle regulators p53, p21, cyclin D1, c‐Fos and CDK2 using Western blot analysis. In addition, the expression of PGC‐1α and the cell proliferation‐related proteins PCNA and phosphate histone H3 was determined by Western blot and immunohistochemical staining analyses. Histone epigenetic modification of the PGC‐1α promoter was investigated through chromatin immunoprecipitation (ChIP) and reverse transcription–quantitative polymerase chain reaction (RT‐qPCR) assays. The impact of PGC‐1α on liver regeneration after PH was further evaluated in PGC‐1α‐knockout mice.ResultsA decreased expression of PGC‐1α and liver regeneration‐related genes in the fibrotic liver was detected after a PH. Histone acetylation at the PGC‐1α promoter led to increases in PGC‐1α expression and the survival rate in the fibrotic group after a PH. PGC‐1α‐mediated liver regeneration was further demonstrated in PGC‐1αf/falbcre+/0 mice.ConclusionTargeting PGC‐1α may represent a strategy to improve the treatment of PH in patients with liver fibrosis.