ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1571007
Therapeutic Potential of Formononetin in Cirrhotic Portal Hypertension: Modulating Hepatic Fibrosis, Macrophage Polarization and Lymphangiogenesis
Provisionally accepted
Zhenghao Wu
Guqing Luo
Hongjie Li
Min Chen
Guangbo Wu
Qiang Fan
Chihao Zhang
Jiwei Yu
Jiayun LinJinbo ZhaoXiaoliang QiHaizhong Huo*
Meng Luo*
Lei Zheng*- Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Background & Aims: Formononetin (FN) has been reported to have anti-fibrotic effects in the kidneys and anti-M1 polarization effects on macrophages. Lymphangiogenesis is closely associated with macrophages, but its role in cirrhosis and portal hypertension (PHT) remains unclear. This study aims to explore the effects of FN on cirrhotic PHT and the disease-related intrahepatic lymphangiogenesis. Methods: In vivo experiments, bile duct ligation (BDL) induced PHT models were conducted in rats, followed by a 4-week FN treatment (50 mg/kg/day) administered via gavage. Hemodynamics, liver fibrosis, infiltration and polarization of intrahepatic macrophages, as well as intrahepatic lymphangiogenesis, were observed. For in vitro experiments, hepatic stellate cells, macrophages and lymphatic endothelial cells were used to observe the multiple effects of FN. Results: FN significantly ameliorated portal pressure in cirrhosis-induced PHT, improved liver function, and reduced liver fibrosis and hepatic stellate cell activation with decreased SMAD3 protein expression. The intrahepatic macrophage infiltration were markedly decreased, and M1-type macrophage polarization was suppressed by FN, accompanied by inhibition of STAT1, STAT3 and GSK-3β signaling pathways. In PHT models, FN reduced VEGF-C and VEGF-D levels in both the liver and blood, inhibiting intrahepatic lymphangiogenesis in portal area. In vitro, high-dose FN significantly inhibited lymphatic endothelial cell proliferation, while the pro-lymphangiogenic effect of conditioned medium from FN-treated M1 macrophages was diminished. Conclusions: FN significantly ameliorates cirrhotic PHT while reducing fibrosis, suppressing macrophage M1 polarization and inhibiting lymphangiogenesis. This may result from its modulation of multiple signaling pathways (SMAD3, STAT1, STAT3 and GSK-3β).
Keywords: portal hypertension, Liver Cirrhosis, macrophages polarization, Lymphangiogenesis, Formononetin
Received: 04 Feb 2025; Accepted: 21 Jul 2025.
Copyright: © 2025 Wu, Luo, Li, Chen, Wu, Fan, Zhang, Yu, Lin, Zhao, Qi, Huo, Luo and Zheng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Haizhong Huo, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Meng Luo, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Lei Zheng, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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