Pinocembrin from Penthorum chinense Pursh suppresses hepatic stellate cells activation through a unified SIRT3-TGF-beta-Smad signaling pathway

The inactivation of hepatic stellate cells (HSCs) has been verified to be an effective therapeutic strategy for treatment of liver fibrosis. Penthorum chinense Pursh has been widely used to protect liver in China; while, the role of P. chinense Pursh in treatment of liver fibrosis is still unexplored. In the current study, the aqueous extract of P. chinense Pursh (PCE) was found to suppress the expressions of fibrotic markers, including collagen I and a smooth muscle actin (alpha-SMA), in human HSCs (LX-2); and its major active constituent, pinocembrin (PIN), was discovered to inhibit the expressions of fibrotic markers in LX-2 cells and rat HSCs (HSC-T6). Further study indicated that PIN suppressed the activation of LX-2 and HSC-T6 cells through elevating the expression and activity of silent mating type information regulation 2 homolog 3 (SIRT3). Via SIRT3, PIN activated superoxide dismutase 2 (SOD2), to alleviate the accumulation of reactive oxygen species (ROS) and inhibit phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt) signaling, resulting in decreased production of transforming growth factor-beta (TGF-beta)and nuclear translocation of the transcription factor Sma- and Mad-related proteins (Smad). Furthermore, PIN activated glycogen synthase kinase 3 beta (GSK3 beta) through SIRT3, to enhance Smad protein degradation. Taken together, PCE and PIN were identified as potential anti-fibrotic agents, which might be well developed as a candidate for treatment of liver fibrosis.