Pterostilbene alleviates liver fibrosis by triggering ferroptosis in activated hepatic stellate cells through regulation of PI3K/Akt signaling pathway.

OBJECTIVES

Liver fibrosis is a risk factor leading to cirrhosis and even liver cancer. Pterostilbene (PTE) is a stilbenoid compound derived from blueberries and grapes. However, whether PTE can alleviate liver fibrosis, inhibit the activation of hepatic stellate cells (HSCs), and its potential mechanisms are still unclear.

MATERIALS AND

METHODS

In vivo, liver fibrosis was induced in mice using carbon tetrachloride (CCl₄) to assess the anti-fibrotic effects of PTE. In vitro, TGF-β1-activated LX-2 cells were treated with PTE, and ferroptosis inhibitors were applied to further examine PTE's anti-fibrotic action.

RESULTS

In vivo, PTE alleviated CCl₄-induced liver injury and inflammation, and reduced the degree of liver fibrosis. In vitro, PTE inhibited LX-2 cell activity and attenuated fibrosis-related protein expression. Further studies revealed that PTE's inhibitory effect on LX-2 cells was associated with ferroptosis, manifested by GSH depletion, MDA generation, ROS production, and lipid peroxidation accumulation. Mechanistically, we found that PI3K/Akt signaling pathway is a critical regulator in PTE-induced ferroptosis in LX-2 cells. After activating the expression of PI3K in LX-2 cells, PTE lost its ability to induce ferroptosis and its anti-fibrotic function.

CONCLUSIONS

PTE inhibits CCl4-induced liver fibrosis by targeting PI3K/Akt to induce ferroptosis in HSCs. These findings indicate that PTE is a promising candidate for the treatment of liver fibrosis.