Anticancer Effect of Icaritin on Prostate Cancer via Regulating Abundance of Akkermansiaceae and Vitamin K2 in Intestinal Fecal

Simple SummaryOur study investigated the mechanisms by which Icaritin (ICT) suppresses prostate cancer (PCa) progression via modulation of the gut microbiome. Using C57BL/6 and TRAMP mouse models, we found that a high-fat diet (HFD) significantly reduced in-testinal Akkermansiaceae abundance and vitamin K2 levels relative to control di-et-fed mice. ICT supplementation in HFD-fed TRAMP mice restored Akkermansiaceae pop-ulations and elevated vitamin K2 levels, concurrently decreasing serum leptin and in-creasing adiponectin concentrations. Direct gavage with Akkermansiaceae similarly elevated vitamin K2 levels, improved adipokine profiles, and extended survival. These findings demonstrate that ICT exerts anti-tumor effects by modulating gut Akker-man-siaceae, thereby enhancing vitamin K2 production and regulating adipokine se-cretion, which supports its clinical potential for PCa treatment.Background:High-fat diet (HFD) induced inflammation and tumorigenesis by altering gut microenvironment and gut microbiome profiles. Vitamin K2 along withAkkermansiaceae, an intestinal symbiote, is involved in anti-tumors including prostate cancer (PCa). Although there have been clinical studies of Icaritin (ICT) for anti-tumor, its detailed mechanism for anti-PCa remains unclear. Here, we explored the effect of ICT on PCa progression that involved altering the mouse gut microbiome.Methods:We used 20 C57BL/6 mice and 85 transgenic adenocarcinomas of mouse prostate (TRAMP) mice as animal models. Then, 16SrRNA pyrophosphate gene sequencing was used to analyze the intestinal fecal microbiome of mice in each group. At the same time, vitamin K2 in fecal samples was determined by High Performance Liquid Chromatography (HPLC), and the content of adipokines leptin and adiponectin in serum was determined by Elisa.Results:It was observed that the relative abundance ofAkkermansiaceae(9.14 ± 2.75% (C57BL/6J-N) vs. 5.66 ± 1.35% (C57BL/6J-HFD); 1.21 ± 0.61% (TRAMP-N) vs. 0.67 ± 0.45% (TRAMP-HFD) (p< 0.05) and vitamin K2 (C57BL/6J-HFD was 0.41-fold to C57BL/6J-N, TRAMP-HFD was 0.71-fold to TRAMP-N) in the intestinal fecal of HFD C57BL/6 and TRAMP were significantly lower than those of control mice. Both the ratio ofAkkermansiaceaeand vitamin K2 in the gut fecal were significantly increased in HFD-fed TRAMP mice supplemented with ICT compared with HFD-fed TRAMP group (p< 0.01). When HFD TRAMP mice were fed withAkkermansiaceaeby gavage, the content of vitamin K2 in the intestinal fecal of the mice was increased, the adipokines leptin in the serum were decreased, but the adiponectin was significantly increased, and the overall survival time of the TRAMP mice was significantly prolonged. Our study shows that ICT rescued the reduction inAkkermansiaceaein the gut microbiota of HFD TRAMP mice. ICT suppresses PCa by modulatingAkkermansiaceaein the gut, increasing vitamin K2, and regulating adipokines leptin and adiponectin secretion.Conclusions:Our study suggested that ICT might regulate abundance ofAkkermansiaceaeto increase vitamin K2 to suppress PCa. This provides theoretical basis and data support for the clinical application of ICT in the treatment of PCa.