Naringenin: A potential therapeutic agent for modulating angiogenesis and immune response in hepatocellular carcinoma

作者：Wenmei Wu, Xiangyu Qiu, Xiaofan Ye, Zhiliang Zhang, Song Xu, Xiuqi Yao, Yunyan Du, Guosheng Wu, Rongxin Zhang, Jinrong Zhu · 发表于：Journal of Pharmaceutical Analysis · 年份：2025 · DOI：10.1016/j.jpha.2025.101254 · 被引用次数：7 · 研究领域：Genomics, phytochemicals, and oxidative stress、Natural product bioactivities and synthesis、Cancer Mechanisms and Therapy

Naringenin (4,5,7-trihydroxyflavonoid) is a naturally occurring bioflavonoid found in citrus fruits, which plays an important role in metabolic syndrome, neurological disorders, cardiovascular diseases. However, the pharmacological mechanism and biological function of naringenin on anti-angiogenesis and anti-tumor immunity have not yet been elucidated. Our study firstly demonstrates that naringenin inhibits the growth of hepatocellular carcinoma (HCC) cells both in vivo and in vitro. naringenin diminishes the ability of HCC cells to induce tube formation and migration of human umbilical vein endothelial cells (HUVECs) and suppresses neovascularization in chorioallantoic membrane assays. Meanwhile, in vivo results demonstrate that naringenin can significantly up-regulating level of CD8 + T cells subsequently increasing the level of immune-related cytokines in the tumor immune microenvironment. Mechanistically, we found that naringenin facilitate the K48-linked ubiquitination and subsequent protein degradation of vascular endothelial growth factor A (VEGFA) and mesenchymal-epithelial transition receptor (c-Met), which reduces the expression of programmed death ligand 1 (PD-L1). Importantly, combination therapy naringenin with PD-L1 antibody or bevacizumab provided better therapeutic effects in liver cancer. Our study reveals that naringenin can effectively inhibit angiogenesis and anti-tumor immunity in liver cancer by degradation of VEGFA and c-Met in a K48-linked ubiquitinati...