Rhapontigenin Suppresses Leptin-Induced Vasculogenic Mimicry by Inhibiting STAT3-Aquaporin-1 Axis in TNBC Cells

<b>Background/Objectives:</b> Vasculogenic mimicry (VM) is a process in which tumor cells form channel structures that resemble blood vessels in shape and function and is increasingly being recognized as a mechanism that contributes to triple-negative breast cancer (TNBC) progression and treatment resistance. Leptin, an adipokine that is elevated in patients with obesity, influences VM in breast cancer. Aquaporin-1 (AQP1), a water and solute channel, mediates leptin-induced VM. Rhapontigenin (Rha) is a stilbene derivative that exhibits diverse biological effects, including antioxidant, anti-inflammatory, and anticancer properties. This study investigated whether Rha inhibits leptin-induced VM and whether the mechanism involves AQP1 in TNBC cells. <b>Methods</b>: Cell viability was measured via MTT assay. mRNA and protein expression levels were measured by RT-qPCR and Western blot analysis, respectively. The DNA-binding activity of the signal transducer and activator of transcription 3 (STAT3) was determined using chromatin immunoprecipitation. Invasion and VM tube formation assays were performed. <b>Results</b>: Rha downregulated leptin-induced AQP1 mRNA and protein expression in TNBC cells without cytotoxicity. Phosphorylation of STAT3 by leptin was decreased after Rha treatment. Rha attenuated leptin-induced STAT3 DNA-binding activity at the AQP1 promoter. In addition, Rha inhibited leptin-induced invasion and VM. Consistent with these effects, the expression levels of invasion- and VM-related proteins and matrix metalloproteinase-2 activity were increased by leptin, which was reduced after Rha treatment. <b>Conclusions</b>: These results indicate that Rha inhibits invasive behavior and VM in TNBC cells by interfering with the leptin-STAT3-AQP1 signaling pathway, suggesting that Rha is a promising therapeutic candidate for the treatment of obesity-associated TNBC.