Apigenin intervenes in liver fibrosis by regulating PKM2-HIF-1α mediated oxidative stress

Biochem Biophys Res Commun. 2024 Aug 20:721:150130. doi: 10.1016/j.bbrc.2024.150130. Epub 2024 May 16.


Apigenin (API) is a natural flavonoid compound with antioxidant, anti fibrotic, anti-inflammatory and other effects, but there is limited research on the effect of API on liver fibrosis. This study aims to explore the effect and potential mechanism of API on liver fibrosis induced by CCl4 in mice. The results indicate that API reduces oxidative stress levels, inhibits hepatic stellate cell (HSC) activation, and exerts anti liver fibrosis effects by regulating the PKM2-HIF-1α pathway. We observed that API alleviated liver tissue pathological damage and collagen deposition in CCl4 induced mouse liver fibrosis model, promoting the recovery of liver function in mice with liver fibrosis. In addition, the API inhibits the transition of Pyruvate kinase isozyme type M2 (PKM2) from dimer to tetramer formation by regulating the EGFR-MEK1/2-ERK1/2 pathway, thereby preventing dimer from entering the nucleus and blocking PKM2-HIF-1α access. This change leads to a decrease in malondialdehyde (MDA) and Catalase (CAT) levels and an increase in glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) levels, as well as total antioxidant capacity (T-AOC) in the liver of liver fibrosis mice. At the same time, API downregulated the expression of α-smooth muscle actin (α-SMA), Vimentin and Desmin in the liver tissue of mice with liver fibrosis, inhibited the activation of HSC, and reduced collagen deposition. These results indicate that API can inhibit HSC activation and alleviate CCl4 induced liver fibrosis by inhibiting the PKM2-HIF-1α pathway and reducing oxidative stress, laying an important foundation for the development and clinical application of API as a novel drug for treating liver fibrosis.

Keywords: API; Hepatic stellate cell; Liver fibrosis; Oxidative stress.

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Antioxidants / pharmacology
  • Apigenin* / pharmacology
  • Apigenin* / therapeutic use
  • Carbon Tetrachloride / toxicity
  • ErbB Receptors
  • Hepatic Stellate Cells / drug effects
  • Hepatic Stellate Cells / metabolism
  • Hepatic Stellate Cells / pathology
  • Hypoxia-Inducible Factor 1, alpha Subunit* / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis* / drug therapy
  • Liver Cirrhosis* / metabolism
  • Liver Cirrhosis* / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Stress* / drug effects
  • Pyruvate Kinase / metabolism
  • Thyroid Hormone-Binding Proteins
  • Thyroid Hormones / metabolism


  • Apigenin
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Pkm protein, mouse
  • Hif1a protein, mouse
  • Pyruvate Kinase
  • Carbon Tetrachloride
  • Thyroid Hormone-Binding Proteins
  • EGFR protein, mouse
  • Thyroid Hormones
  • Antioxidants
  • ErbB Receptors