Acetylbinankadsurin A Decreases Macrophage Glycolysis and Pro-Inflammatory Phenotype Polarization via Inhibiting HIF-1α to Alleviate Hepatic Fibrosis in Mice

Hepatic fibrosis is a prevalent pathological process of chronic liver injury, which can progress to cirrhosis and hepatocellular carcinoma, representing a major cause of mortality in patients with chronic liver disease. <i>Kadsura coccinea</i> (Lem.) A. C. Smith possesses pharmacological properties, including antitumor and anti-inflammatory effects, and is primarily used to treat rheumatism, hepatotoxicity injury, and chronic hepatitis. Acetylbinankadsurin A (ACBA) is a natural compound extracted from the roots of <i>Kadsura coccinea</i>. However, there have been few studies on the pharmacological activity of ACBA. This study aimed to investigate whether ACBA decreases macrophage glycolysis and pro-inflammatory phenotype polarization by inhibiting HIF-1α to alleviate hepatic fibrosis in mice. In this study, CCl₄-induced mouse liver fibrosis models and lipopolysaccharide (LPS)-induced THP-1 monocytic cell lines were utilized to simulate macrophage polarization. Techniques such as Western blotting and immunofluorescence were applied to analyze macrophage glycolysis and phenotypes. Our findings revealed that ACBA alleviated CCl₄-induced hepatic fibrosis in mice and suppressed LPS-induced M1 macrophage polarization. We observed that ACBA significantly reduced the expression of HIF-1α and macrophage glycolysis in liver fibrosis tissue and LPS-induced M1 macrophages. Furthermore, molecular docking, molecular dynamics simulations, and SPR assays demonstrated that there are three sites on the HIF-1α amino acid residues that can stably bind with ACBA in vitro. In conclusion, these results suggest that ACBA inhibits the activity of HIF-1α, thereby decreasing macrophage glycolysis and the pro-inflammatory phenotype, which alleviates hepatic fibrosis in mice.