Silencing of CD147 inhibits hepatic stellate cells activation related to suppressing aerobic glycolysis via hedgehog signaling

Hepatic stellate cells (HSCs) activation is a key step that promotes hepatic fibrosis. Emerging evidence suggests that aerobic glycolysis is one of its important metabolic characteristics. Our previous study has reported that CD147, a glycosylated transmembrane protein, contributes significantly to the activation of HSCs. However, whether and how it is involved in the aerobic glycolysis of HSCs activation is unknown. The objective of the present study was to validate the effect of CD147 in HSCs activation and the underlying molecular mechanism. Our results showed that the silencing of CD147 decreased the expression of α-smooth muscle-actin (α-SMA) and collagen I at both mRNA and protein levels. Furthermore, CD147 silencing decreased the glucose uptake, lactate production in HSCs, and repressed the lactate dehydrogenase (LDH) activity, the expression of hexokinase 2 (HK2), glucose transporter 1 (Glut1). The effect of galloflavin, a well-defined glycolysis inhibitor, was similar to CD147 siRNA. Mechanistically, CD147 silencing suppressed glycolysis-associated HSCs activation through inhibiting the hedgehog signaling. Moreover, the hedgehog signaling agonist SAG could rescue the above effect of CD147 silencing. In conclusion, CD147 silencing blockade of aerobic glycolysis via suppression of hedgehog signaling inhibited HSCs activation, suggesting CD147 as a novel therapeutic target for hepatic fibrosis.