2. Academic Validation
  3. Fangchinoline suppresses melanoma metastasis by inducing senescence of circulating tumor cells

Fangchinoline suppresses melanoma metastasis by inducing senescence of circulating tumor cells

  • Biomed Pharmacother. 2025 Dec:193:118770. doi: 10.1016/j.biopha.2025.118770.
Junhao Chen 1,  Jianyang Hu 2,  Jiapeng He 3,  Binyu Zhang 3,  Haoyuan Tan 3,  Qiqi Wang 4,  Hailiang Hu 3,  Suling Xu 5,  Chris Soon Heng Tan 4,  Jianglin Zhang 6,  Xin Hong 7
Affiliations

Affiliations

  • 1 Dapartment of Dermatology, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, 518020, China; Department of Biochemistry, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, Guangdong, China; Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen, Guangdong, China.
  • 2 Department of Biochemistry, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, Guangdong, China; Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen, Guangdong, China. Electronic address: [email protected].
  • 3 Department of Biochemistry, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
  • 4 Department of Chemistry, College of Science, Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen 518055, China.
  • 5 Department of Dermatology, The First Affiliated Hospital of Ningbo University, Ningbo University, Ningbo 315010, China.
  • 6 Dapartment of Dermatology, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, 518020, China. Electronic address: [email protected].
  • 7 Department of Biochemistry, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, Guangdong, China; Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen, Guangdong, China. Electronic address: [email protected].
PMID: 41242135 DOI: 10.1016/j.biopha.2025.118770
Abstract

Melanoma metastasis is largely driven by blood-borne dissemination of circulating tumor cells (CTCs), yet effective strategies to target them remain limited. Using patient-derived CTC experimental systems, we identified Fangchinoline, a bisbenzylisoquinoline alkaloid extracted from Stephania tetrandra S.Moore, as a potent inducer of CTC senescence, characterized by elevated p21 expression, stable G0/1 cell cycle arrest, reduced Lamin B1 expression, the upregulation of senescence-associated secretory phenotype (SASP) signatures, and elevated mitochondrial ROS. In CDX mouse models, Fan significantly inhibited systemic metastasis and reduced the burden of CTCs without notable toxicity. By Proteomic Isothermal Shift Assay, we identified FAU (FAU ubiquitin-like and ribosomal protein S30 fusion) as a novel target of Fangchinoline that mediated the induction of senescence in melanoma CTCs. Furthermore, RNA-seq analysis revealed that Cholesterol biosynthesis pathway was remarkably upregulated upon Fangchinoline treatment. Notably, the lipid-lowering drug Simvastatin substantially sensitized Fangchinoline-treated CTCs to undergo Apoptosis. Together, these findings identified a novel role of Fangchinoline in inducing CTC senescence and metastasis suppression, provided a mechanistic basis for devising a "One-two punch sequential therapy" using Fangchinoline followed by Simvastatin as a potential strategy to treat melanoma metastasis.

Keywords

Circulating Tumor Cells; FAU; Fangchinoline; Melanoma metastasis; Senescence; Simvastatin.

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