{Reference Type}: Journal Article
{Title}: Glycyrrhizic acid ameliorates hepatic fibrosis by inhibiting oxidative stress via AKR7A2.
{Author}: Wang Q;Lu T;Song P;Dong Y;Dai C;Zhang W;Jia X;Guo Z;Zhao M;Zhang J;Wang P;Wang J;Guo Q;
{Journal}: Phytomedicine
{Volume}: 133
{Issue}: 0
{Year}: 2024 Oct 14
{Factor}: 6.656
{DOI}: 10.1016/j.phymed.2024.155878
{Abstract}: <B>BACKGROUND: </B>Hepatic fibrosis is a reversible pathological phenomenon caused by the abnormal proliferation of connective tissues in the liver for self-repair after persistent liver injury. Among these tissues, the activation status of hepatic stellate cells (HSCs) is crucial. Glycyrrhizic acid (GA) agents have been proven to have excellent anti-fibrosis effects, but their targets are unclear.<BR><B>OBJECTIVE: </B>To investigate the anti-hepatic fibrosis effect of GA and its target in activated HSCs.<BR><B>METHODS: </B>A mouse model of hepatic fibrosis was prepared with 20 % carbon tetrachloride (CCl4) and GA was administered continuously for 4 weeks. Subsequently, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), type Ⅲ procollagen peptide (P III P), laminin (LN), hyaluronic acid (HA), and type Ⅳ collagen (Col Ⅳ) were measured. Liver tissues were subjected to hematoxylin and eosin (HE), Masson, and Sirius red staining and proteome sequencing analysis. Based on LX-2 cells, activity-based protein profiling (ABPP) was used to investigate the potential targets of GA, which was further validated by the cellular thermal shift assay (CETSA), immunofluorescence co-localization, molecular docking, small interfering RNA (siRNA) and western blot (WB) assays.<BR><B>RESULTS: </B>In vivo, GA significantly reduced serum ALT, AST, HA, P III P, Col IV, and LN levels. HE, Masson, and Sirius red staining showed that GA significantly ameliorated hepatic inflammatory response and collagen deposition in CCl4-treated mice. Proteome sequencing results showed that GA mainly regulated glutathione S-transferase family members involved in glutathione metabolism. In vitro, GA significantly inhibited LX-2 cell proliferation and reduced reactive oxygen species accumulation. ABPP suggested that aldo-keto reductase family 7 member A2 (AKR7A2) was the major binding protein of GA in LX-2 cells. CETSA, fluorescence co-localization, molecular docking, and surface plasmon resonance further validated GA binding to AKR7A2. The WB results showed that GA up-regulated AKR7A2 expression both in vitro and in vivo and was corroborated by siRNA experiments.<BR><B>CONCLUSIONS: </B>GA targeted AKR7A2 in LX-2 cells to defend against sustained oxidative stress injury, thereby inhibiting the proliferation of activated HSCs and reversing hepatic fibrosis.