Quercetin Alleviates Liver Fibrosis via Neutrophil Infiltration Mediated by Glycolysis of Liver Sinusoidal Endothelial Cells

Abstract

Abstract Liver fibrosis is a prevalent characteristic in various chronic liver diseases, and glycolysis plays a pivotal role in this process. Quercetin (QE), as a natural flavonoid, has been reported to effectively regulate glycolysis. This study aimed to elucidate the effects of QE on liver fibrosis and its specific underlying mechanism.The results indicated that QE alleviated carbon tetrachloride (CCl4)-induced liver injury and fibrosis by improving pathological manifestations, thereby reducing the activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBIL), as well as decreasing the serum levels of hyaluronic acid (HA), laminin (LN), and procollagen type III (PCIII). Additionally, QE downregulated lactate production in mice with liver fibrosis, as well as the mRNA and protein levels of rate-limiting enzymes in glycolysis such as PKM2, PFKP, and HK2. It also diminished the expression and activity of PKM2, PFKP, and HK2 in liver sinusoidal endothelial cells (LSECs), along with reducing glucose consumption and lactate production. Immunohistochemistry and immunofluorescence revealed that QE inhibited CXCL1 secretion in LSECs and impeded neutrophil recruitment. In summary, QE demonstrated its therapeutic potential for liver fibrosis by mitigating neutrophil infiltration through the inhibition of LSEC glycolysis.