Emodin promotes GSK-3β-mediated PD-L1 proteasomal degradation and enhances anti-tumor immunity in hepatocellular carcinoma

作者：Xuemei Yang, Weiguang Chen, Haitao Sun, Weicong Chen, Wei Xu, Chunyu He, Yang Liu, Ying Kuang, Yuanfang Ma, Binglian Zhong, Chaojie Li, G. Li, Qingfeng Du, Songqi He · 发表于：Chinese Medicine · 年份：2025 · DOI：10.1186/s13020-025-01146-6 · 被引用次数：8 · 研究领域：Phytochemistry and biological activity of medicinal plants、Pharmacological Effects of Natural Compounds、Heat shock proteins research

Abstract Background Programmed death-ligand 1 (PD-L1), a prominent immune checkpoint, interacts with programmed death protein-1 (PD-1) on cytotoxic T cells within tumors and promotes immune evasion. Emodin, which is known to destabilize PD-L1 in breast cancer, has great potential for enhancing anti-tumor immunity. However, whether emodin can modulate PD-L1 levels in hepatocellular carcinoma (HCC) and enhance anti-tumor immune response remains unclear. Materials and methods PD-L1 levels were assessed by western blot and RT-qPCR, the degradation mechanism was analyzed using specific inhibitors. Network pharmacology, molecular docking, and glycogen synthase kinase-3 beta (GSK-3β) modulation analyzes were performed to validate emodin’s target. In vivo anti-tumor effects were evaluated in H 22 subcutaneous tumor model, and CD8 + T cells and RNA-seq data were analyzed. The synergistic effects of emodin and an anti-PD-L1 antibody were assessed. Results Emodin effectively reduced PD-L1 levels in H 22 cells and increased anti-tumor activity in an H 22 subcutaneous tumor model by promoting CD8 + T cells infiltration and TNF-α, IFN-γ, and granzyme B secretion. Mechanistically, emodin accelerated PD-L1 degradation through the proteasome pathway in both mouse and human HCC cell lines, as confirmed by the use of proteasome, lysosome and autophagy inhibitors. Network pharmacology analysis and molecular docking revealed that GSK-3β, a key regulator of PD-L1 degradation, is a target of emodin...