Dioscin initiates dual roles in bladder cancer progression via miR-195–5p/FASN/SLC3A2 axis-mediated cell death mechanisms

Emerging evidence highlights dioscin, a bioactive compound derived from Dioscoreaceae plants, as a promising antitumor agent, yet its regulatory mechanisms in bladder cancer and interaction with microRNAs remain unclear. This study systematically investigated dioscin's dual roles in bladder cancer progression through in vitro and in vivo models. Functional assays demonstrated that dioscin significantly upregulated miR-195–5p expression in bladder cancer cells, while both dioscin and miR-195–5p suppressed T24/EJ cell proliferation, migration, and invasion. Mechanistically, RNA-seq and molecular docking revealed dioscin directly bound to fatty acid synthase (FASN), which then regulated the SLC3A2 expression. Strikingly, miR-195–5p mimic transfection downregulated FASN, whereas its inhibitor reversed this effect, confirming miR-195–5p's pivotal role in dioscin-mediated FASN/SLC3A2 inhibition. Notably, dioscin potentiated cisplatin's antitumor efficacy against both BIU87 and cisplatin-resistant BIU87 bladder cancer cells at low micromolar concentrations. Intriguingly, the bladder cancer cell induced by dioscin could be counteracted by inhibitors of apoptosis, necroptosis, and ferroptosis, particularly in the presence of gap junction inhibitor carbenoxolone. However, in vivo studies uncovered a paradoxical duality: dioscin enhanced N-methyl-N-nitrosourea (MNU)-induced bladder tumorigenesis. Its combination with MNU exacerbated renal toxicity and bladder stone formation in rats, accompanied by elevated creatinine and uric acid levels. Crucially, dioscin exhibited cytotoxicity against normal urothelial (SV-HUC-1) and renal (MDCK) cells, warranting cautious therapeutic application. These findings unveil a novel miR-195–5p/FASN/SLC3A2 axis through which dioscin initiates bladder cancer cell death, while highlighting dual roles of dioscin in bladder cancer and the necessity for dosage optimization to balance its antitumor potency and off-target toxicity.