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Rhapontigenin suppresses endometrial cancer metastasis via modulation of

the ANGPTL4–ATF3 regulatory axis

,2
1
Rong-Xuan Chen, Chia-Liang Lin*

1 Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan
2 Department of Biochemistry, School of Medicine, Chung Shan Medical University,
Taichung, Taiwan
* E-mail: t03742@csmu.edu.tw

Abstract
Endometrial cancer (EC) is one of the most prevalent gynecological malignancies, and its
incidence continues to rise worldwide. Although surgery and chemoradiotherapy remain the
mainstay treatments, effective options for advanced or metastatic EC are still limited. Thus,
identifying novel therapeutic agents and elucidating their molecular mechanisms are of
significant clinical importance. Rhapontigenin (RhA), a stilbenoid compound derived from
Rheum species, has been reported to exert antioxidant, anti-inflammatory, and anticancer
activities. Previous studies revealed that RhA suppresses angiogenesis and invasion by targeting
the HIF-1α and TGF-β signaling pathways. However, its therapeutic potential and mechanisms
of action in EC remain largely unexplored. In this study, we investigated the anti-metastatic
effects of RhA in three EC cell lines. Treatment with 50 μM RhA exhibited no significant
cytotoxicity, but markedly suppressed cell migration and invasion in a dose-dependent manner,
indicating a role in attenuating metastatic progression. To uncover the underlying mechanisms,
RNA sequencing combined with TCGA dataset analysis identified ANGPTL4 and ATF3 as
potential RhA-regulated genes. Functional assays demonstrated that recombinant ANGPTL4
enhanced EC cell migration and reduced ATF3 expression, while RhA treatment reversed these
effects. These findings highlight ANGPTL4 as a primary molecular target of RhA, mediating
the regulation of ATF3 and contributing to the suppression of EC metastasis. In conclusion, our
results provide the first evidence that RhA attenuates EC metastasis through modulation of the
ANGPTL4–ATF3 regulatory axis. These findings not only establish RhA as a promising anti-
metastatic candidate for endometrial cancer but also suggest ANGPTL4 as a potential
therapeutic target for future precision medicine strategies.

Keywords: Rhapontigenin (RhA); Endometrial Cancer (EC); Metastasis; ANGPTL4–ATF3
axis