Oxymatrine Inhibits PD-L1 by Downregulating IFN-γ to Promote Ferroptosis and Enhance Anti-PD-L1 Efficacy in Liver Cancer.

PURPOSE

Oxymatrine has potent anti-cancer activity, but its exact mechanism in liver cancer remains elusive. The present study was designated to explore oxymatrine's effect and the potential mechanism on Programmed cell death-ligand 1 (PD-L1) expression and ferroptosis in liver cancer.

METHODS

Oxymatrine's influence on PD-L1 expression and ferroptosis-related proteins in liver cancer cells was explored in vitro and in vivo utilizing Western blotting, qRT-PCR, immunofluorescence, ELISA, H&E staining, immunohistochemistry, as well as detection of Fe, ROS, and MDA.

RESULTS

The in-vivo results showed that xenotransplanted tumor mice with drug interventions (oxymatrine, anti-PD-L1, and combination groups) exhibited inhibited tumor growth compared to control mice. Relative to anti-PD-L1 administration alone, the combined treatment inhibited tumor growth more significantly, along with reduced interferon-γ (IFN-γ) expression in peripheral blood and remarkably increased tumor immune lymphocyte (CD4 T and CD8 T) infiltration in cancer tissues. Meanwhile, PD-L1, xCT, and GPX4 protein levels in the combination group were significantly downregulated. According to the in vitro results, IFN-γ promoted PD-L1, xCT, and GPX4 protein levels in liver cancer cell lines. Oxymatrine reversed IFN-γ-induced upregulation of PD-L1 expression; moreover, it downregulated xCT and GPX4 protein levels in liver cancer cells and promoted intracellular Fe, ROS, and MDA levels.

CONCLUSION

Oxymatrine promotes tumor immune response and ferroptosis in liver cancer by downregulating IFN-γ and synergistically enhances the inhibitory effect of anti-PD-L1 on liver cancer.