ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Ethnopharmacology
This article is part of the Research TopicNatural Medicines for Metabolic Diseases – Computational and Pharmacological Approaches, Volume IIView all 6 articles
Multi-Omics study of the anti-colorectal cancer mechanisms of formononetin in Hedysari Radix
Provisionally accepted
Jun Rao1
Xing Wang2
Tanxiu Chen3
Mingzi Mo4Conglong Xu5
So-Yi Chang6
Ssu-Wei Hsu6Xiaoqun Han4
Ching-Hsien Chen6*
Zhi Zheng2*- 1Jiangxi Cancer Hospital, Nanchang, China
- 2Jiangxi Provincial People's Hospital, Nanchang, China
- 3The First Affiliated Hospital of Nanchang University, Nanchang, China
- 4Yichun University, Yichun, China
- 5Jiangxi Jingde Traditional Chinese Medicine Co., Ltd., China, China
- 6University of California Davis, Davis, United States
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Background: Hedysari Radix (HR), commonly known as Hong-Qi in Chinese, is a traditional Chinese herbal medicine recognized for possessing anti-inflammatory and anti-tumor properties. While the polysaccharides in HR have been extensively studied, other HR metabolites and their potential anti-tumor properties remain largely unknown. Methods: We employed a multi-omics strategy integrating metabolomics, network analysis, proteomics, phosphoproteomics, and molecular docking to identify HR metabolites with anti-colorectal cancer (CRC) property and investigate underlying mechanisms. Results: Using mass spectrometry-based metabolomics, we identified 1,292 metabolites across eight processed HR products. Key metabolites including medicarpin, formononetin, naringenin, and quercetin were validated via the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Notably, formononetin-derived metabolites were significantly enriched during HR processing. The metabolite-metabolite correlation analysis revealed key compounds such as flavonoids and formononetin. Subsequent network analysis combined with label-free data-independent acquisition (DIA) proteomics and phosphoproteomics in colon cancer cells identified 194 potential targets, 291 differentially expressed proteins, and 1,535 phosphorylated proteins that were regulated by formononetin. Cell-surface enzymes carbonic anhydrase IX (CA9) and membrane metalloendopeptidase (MME) were consistently identified in different analyses as key targets, and molecular docking results confirmed their strong binding to formononetin. Bioinformatics analyses further revealed significant enrichment of cancer-associated pathways, including PI3K-Akt, Hippo, HIF-1 signaling, and cholesterol metabolism upon formononetin treatment. Conclusion: The findings provide novel insights into the HR metabolome and reveal the multi-targeting roles of formononetin in CRC development, laying the foundation for developing new CRC therapeutic strategies.
Keywords: anti-tumor, CA9, colorectal cancer, Formononetin, Hedysari Radix, MME
Received: 18 Jun 2025; Accepted: 10 Dec 2025.
Copyright: © 2025 Rao, Wang, Chen, Mo, Xu, Chang, Hsu, Han, Chen 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:
Ching-Hsien Chen
Zhi Zheng
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