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Icaritin suppresses colorectal cancer invasion and metastasis through regulation of epithelial-mesenchymal transition and the Wnt/β-catenin signaling pathway
Xiang Li, Yan-Jiao Li, Dan-Dan Ren, Mei Yuan, Ya-Ru Qi, Hui-Wen Li, Yi Zhang, Ruo-Yu Wang
Xiang Li, Graduate School, Dalian Medical University, Dalian 116044, Liaoning Province, China
Yan-Jiao Li, Mei Yuan, The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China
Dan-Dan Ren, Office of Clinical Drug Trial Institutions, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China
Ya-Ru Qi, Hui-Wen Li, Yi Zhang, Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China
Ruo-Yu Wang, Department of Oncology, Dalian Medical University, Dalian 116044, Liaoning Province, China
Author contributions: Li X was responsible for figures and tables; Li X, Li YJ, and Ren DD were responsible for methodology; Li X, Li YJ, and Wang RY were responsible for conceptualization; Li X, Li YJ, Ren DD, Yuan M, Qi YR, Li HW, and Zhang Y were responsible for investigation; Li X, Li YJ, Ren DD, Yuan M, Qi YR, Li HW, Zhang Y, and Wang RY were responsible for writing the original draft; Wang RY was responsible for supervision; all authors reviewed the results and approved the final version of the manuscript.
Institutional animal care and use committee statement: The studies involving animals were approved by the Ethics Committee of the Affiliated Zhongshan Hospital of Dalian University, No. DW2024-023-01.
Conflict-of-interest statement: The authors declare no conflict of interest in publishing the manuscript.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: Not applicable.
Corresponding author: Ruo-Yu Wang, Professor, Department of Oncology, Dalian Medical University, No. 9 West Section of Lushun South Road, Dalian 116044, Liaoning Province, China.
wangruoyu@dlu.edu.cn
Received: October 24, 2025
Revised: November 18, 2025
Accepted: January 26, 2026
Published online: May 15, 2026
Processing time: 203 Days and 16 Hours
BACKGROUND
Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, and treatment for advanced disease remains challenging. The natural compound icaritin has demonstrated anti-tumor properties, however its effects on CRC metastasis are not fully understood.
AIM
To investigate the inhibitory effects of icaritin on CRC and its underlying mechanism of action.
METHODS
The impact of icaritin on CRC cell invasion and migration was evaluated using in vitro and in vivo approaches. The viability of HCT116 and SW620 cells was assessed using the cell counting kit-8 assay. Epithelial-mesenchymal transition and Wnt/β-catenin signaling related proteins were analyzed by western blotting and immunofluorescence. Cell migration and invasion were evaluated using Transwell assays. Additionally, an orthotopic xenograft tumor model was established to provide further insights.
RESULTS
Icaritin significantly inhibited HCT116 and SW620 cell proliferation in a time-dependent manner and promoted apoptosis, as determined by flow cytometry analysis of apoptotic markers. It also suppressed cell migration and invasion. At the molecular level, icaritin downregulated the expression of N-cadherin, Snail, β-catenin, matrix metalloproteinase 2, and matrix metalloproteinase 9, while upregulating E-cadherin and adenomatous polyposis coli. In a mouse xenograft model, icaritin treatment significantly reduced tumor volume and weight compared to the control group.
CONCLUSION
Icaritin inhibits CRC cell invasion and metastasis by preventing epithelial-mesenchymal transition and suppressing the Wnt/β-catenin signaling pathway, highlighting its potential as a therapeutic agent for CRC.
Core Tip: This study demonstrates that the clinical anti-cancer agent icaritin potently inhibits colorectal cancer metastasis by preventing epithelial-mesenchymal transition and suppressing the Wnt/β-catenin signaling pathway. We provide novel mechanistic evidence that icaritin downregulates key metastatic drivers like N-cadherin, Snail, and matrix metalloproteinase 9 while restoring E-cadherin expression. These findings, validated in orthotopic mouse models, position icaritin as a promising therapeutic candidate for targeting advanced and metastatic colorectal cancer.
