Formosanin C induces autophagy-mediated cell death in hepatocellular carcinoma through activating DUSP1/AMPK/ULK1/Beclin1 signaling pathway

Zhikai Wen; Jinxia Qi; Qingqing Ruan; Chunmei Wen; Gang Huang; Zhan Yang; Jiale Xu; Zongjing Chen; Jie Deng

doi:10.1016/j.phymed.2025.156404

Formosanin C induces autophagy-mediated cell death in hepatocellular carcinoma through activating DUSP1/AMPK/ULK1/Beclin1 signaling pathway

Phytomedicine. 2025 Jan 22:138:156404. doi: 10.1016/j.phymed.2025.156404. Online ahead of print.

Authors

Zhikai Wen¹, Jinxia Qi², Qingqing Ruan³, Chunmei Wen³, Gang Huang⁴, Zhan Yang⁵, Jiale Xu³, Zongjing Chen⁶, Jie Deng⁷

Affiliations

¹ Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China; Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
² Biobank, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, PR China.
³ Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China.
⁴ Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China; Department of thoracic surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
⁵ School of Stomatology, Wenzhou Medical University, Wenzhou 325000, China.
⁶ Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: czjasq@sina.com.
⁷ Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China. Electronic address: dengjiewz@163.com.

PMID: 39862789
DOI: 10.1016/j.phymed.2025.156404

Abstract

Background: Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and is associated with poor survival. Formosanin C (FC) is a diosgenin glycoside extracted from Paris polyphylla. Therapeutic effects of FC against HCC malignancies remain unclear.

Purpose: This study aimed to understand the anti-HCC effects of FC and to disclose the underlying mechanisms.

Study design: We evaluated the effects of FC on HCC malignancies by using two HCC cell lines, HepG2 and Huh-7, and a xenograft model.

Methods: Multiple assessment methods were used, including CCK-8, colony formation, flow cytometry, wound healing, transwell and Western blot. Bioinformatic analyses such as network pharmacology were also employed. Xenograft mouse model was used to evaluate in vivo efficacy.

Results: FC treatment remarkedly suppressed HepG2 and Huh-7 cell proliferation, migration and invasion, and induced cell apoptosis. Such anti-HCC effects of FC mainly attributed to the upregulation of DUSP1 expression and the subsequent activation of autophagy via AMPK/ULK1/Beclin1 axis. Inhibition of autophagy weakened the therapeutic effects of FC. Xenograft model analysis provided in vivo evidence that FC suppressed HCC tumor growth via DUSP1.

Conclusions: FC is therapeutically effective to suppress HCC malignancies principally via activation of the DUSP1/AMPK/ULK1/Beclin1-mediated autophagy. Our findings provide a novel promising drug candidate for treating HCC.

Keywords: Autophagy; DUSP1; Formosanin C; hepatocellular carcinoma.