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

Abstract

Yixi Nong,1– 4,* Houji Qin,2,3,* Liyan Wei,2,5 Xi Wei,2,5 Jiannan Lv,2,3 Xiaoyi Huang,6 Biaoliang Wu1,2,4,7 1The First Clinical Medical College of Jinan University, Guangzhou, 510000, People’s Republic of China; 2Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, 533000, People’s Republic of China; 3Department of Infectious Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, 533000, People’s Republic of China; 4National Immunological Laboratory of Traditional Chinese Medicine, Baise, Guangxi, 533000, People’s Republic of China; 5Health Management Center, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, 533000, People’s Republic of China; 6Youjiang Medical University for Nationalities, Baise, Guangxi, 533000, People’s Republic of China; 7Department of Endocrinology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, 533000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Biaoliang Wu, Department of Endocrinology, Affiliated Hospital of Youjiang Medical University for Nationalities, 18 Zhongshan second Road, Baise, Guangxi, 533000, People’s Republic of China, Email [email protected]: 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 Fe2+, 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 Fe2+, 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.Keywords: oxymatrine, PD-L1, interferon-γ, ferroptosis, anti-PD-L1

Keywords

• oxymatrine
• pd-l1
• interferon-γ
• ferroptosis
• anti-pd-l1