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

Wenmei Wu; Xiangyu Qiu; Xiaofan Ye; Zhiliang Zhang; Siguo Xu; Xiuqi Yao; Yinyi Du; Geyan Wu; Rongxin Zhang; Jinrong Zhu

doi:10.1016/j.jpha.2025.101254

Volume 15 Issue 9

Sep. 2025

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Wenmei Wu, Xiangyu Qiu, Xiaofan Ye, Zhiliang Zhang, Siguo Xu, Xiuqi Yao, Yinyi Du, Geyan Wu, Rongxin Zhang, Jinrong Zhu. Naringenin: A potential therapeutic agent for modulating angiogenesis and immune response in hepatocellular carcinoma[J]. Journal of Pharmaceutical Analysis, 2025, 15(9): 101254. doi: 10.1016/j.jpha.2025.101254

Citation:

Wenmei Wu, Xiangyu Qiu, Xiaofan Ye, Zhiliang Zhang, Siguo Xu, Xiuqi Yao, Yinyi Du, Geyan Wu, Rongxin Zhang, Jinrong Zhu. Naringenin: A potential therapeutic agent for modulating angiogenesis and immune response in hepatocellular carcinoma[J]. Journal of Pharmaceutical Analysis, 2025, 15(9): 101254. doi: 10.1016/j.jpha.2025.101254

Citation:

Wenmei Wu, Xiangyu Qiu, Xiaofan Ye, Zhiliang Zhang, Siguo Xu, Xiuqi Yao, Yinyi Du, Geyan Wu, Rongxin Zhang, Jinrong Zhu. Naringenin: A potential therapeutic agent for modulating angiogenesis and immune response in hepatocellular carcinoma[J]. Journal of Pharmaceutical Analysis, 2025, 15(9): 101254. doi: 10.1016/j.jpha.2025.101254

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

doi: 10.1016/j.jpha.2025.101254

a. Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, China;
b. Biomedicine Research Centre, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510000, China

Funds:

This work was supported by National Natural Science Foundation of China (Grant No.: 82103637), Medical Science and Technology Research Foundation of Guangdong Province, China (Grant No.: A2024066), Science and Technology Projects in Guangzhou, China (Grant No.: 2023A04J0862), Discipline Excellence Program of Guangdong Pharmaceutical University, China (Grant No.: 2024QZ06), and Guangzhou Municipal Science and Technology Project, China (Grant Nos.: 2024A04J3475 and 2025A03J3756).

Received Date: Sep. 10, 2024
Accepted Date: Feb. 27, 2025
Rev Recd Date: Feb. 14, 2025
Publish Date: Sep. 30, 2025

Abstract

Abstract

Naringenin (4,5,7-trihydroxyflavonoid) is a naturally occurring bioflavonoid found in citrus fruits, which plays an important role in metabolic syndrome, neurological disorders, and 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 chicken chorioallantoic membrane (CAM) assays. Meanwhile, in vivo results demonstrate that naringenin can significantly upregulate 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 factor (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 ubiquitination manner. This work enlightens the potential effect of naringenin as a promising therapeutic strategy against anti-angiogenesis and anti-tumor immunity in HCC.
- Naringenin,
- VEGFA,
- c-Met,
- PD-L1,
- Angiogenesis,
- Immunosuppress,
- Hepatocellular carcinoma

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References(39)

References

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