Dietary supplementation with <i>Ganoderma lucidum</i> polysaccharide enhances the anti-metastatic effect of metformin and protects intestinal barrier integrity

Abstract Castration-resistant prostate cancer (CRPC) is an aggressive disease with a high propensity for metastasis and limited therapeutic options. This study investigates the potential of a combined regimen using Ganoderma lucidum polysaccharide (GLP), a bioactive food component derived from the edible Linzhi mushroom, and metformin (MET) in the treatment of CRPC, with a particular focus on metastasis and intestinal barrier function. We found that GLP and MET synergistically inhibited the migration of CRPC cells (PC3, DU145) in vitro. The combination treatment profoundly suppressed epithelial-mesenchymal transition (EMT), as evidenced by increased E-cadherin and decreased N-cadherin, Snail, MMP2, and MMP9 levels. In a mouse model of metastasis using tail vein injection of PC3-luc cells, the GLP/MET combination significantly reduced the incidence and burden of multi-organ and bone metastases, as quantified by bioluminescence imaging, and extended tumor-free survival. Interestingly, from a food safety and health perspective, while MET monotherapy failed to protect the gut, GLP alone and co-administration effectively preserved intestinal barrier integrity. This was demonstrated by the restoration of goblet cells, increased MUC2 expression, and upregulation of tight junction proteins (ZO-1 and occludin), alongside a reduction in macrophage-driven inflammation in colon tissues. Our findings indicate that GLP not only enhances the anti-metastatic efficacy of MET but also ameliorates concomitant intestinal damage. This study highlights the promise of GLP as a safe dietary adjuvant to conventional therapeutics, offering a strategy to improve CRPC management while enhancing gastrointestinal tolerance.