Salvianolic acid B antagonizes hepatocarcinogenesis by inhibiting the p300/pSmad2 complex

E1A-binding protein p300 (p300)/CREB-binding protein (CBP) and phosphorylated Smad2 (pSmad2C/L) are highly activated in hepatocellular carcinoma (HCC), but their relationship remains unclear. Salvianolic (Sal B) exhibits potential anti-HCC activities. We previously reported Sal B downregulates p300/CBP and pSmad2C/L, thereby inhibiting hepatic stellate cell activation and exerting anti-fibrotic effects. Given that hepatic fibrosis is a vital early stage of HCC, we hypothesized that the anti-HCC activities of Sal B are likely to be correlated with p300/CBP and pSmad2C/L. Therefore, we employed diethylnitrosamine (DEN)/carbon tetrachloride (CCl 4 )/ethanol (C 2 H 5 OH)-induced HCC mice and TGF-β1-stimulated HepG2 and HuH-7 cells to explore Sal B intervention. Meanwhile, co-immunoprecipitation and nuclear-cytoplasmic fractionation were used to assess the binding and subcellular localization of p300 with pSmad2C/L. This study revealed that Sal B significantly enhanced hepatic function, ameliorated histopathological abnormalities, and downregulated p300/CBP and pSmad2C/L protein levels in DEN/CCl 4 /C 2 H 5 OH-induced HCC mouse model. Meanwhile, Sal B suppressed proliferation and invasion in both HepG2 and HuH-7 cells, reduced p300/CBP mRNA and protein expression, and decreased pSmad2C/L protein levels. Additionally, Sal B suppressed the nuclear expression of p300, pSmad2C and pSmad2L, and p300 was found to specifically interact with pSmad2C. Collectively, these data illustrated that Sal B might antagonize hepatocarcinogenesis via inhibiting p300/pSmad2 complex, providing a molecular basis for its therapeutic potential against HCC.