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

  • Phytomedicine. 2025 Mar:138:156404. doi: 10.1016/j.phymed.2025.156404.
Zhikai Wen  1 ,  Jinxia Qi  2 ,  Qingqing Ruan  3 ,  Chunmei Wen  3 ,  Gang Huang  4 ,  Zhan Yang  5 ,  Jiale Xu  3 ,  Zongjing Chen  6 ,  Jie Deng  7
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: [email protected].
  • 7. Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China. Electronic address: [email protected].
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.
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