Fangchinoline suppresses melanoma metastasis by inducing senescence of circulating tumor cells

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.