Mevalonate Metabolic Reprogramming Drives Cisplatin Resistance in Bladder Cancer: Mechanisms and Therapeutic Targeting.

Introduction: Dysregulation of mevalonate metabolism is a hallmark of tumorigenesis and therapy resistance across malignancies, though its role in bladder cancer remains unclear. This study aimed to elucidate its impact on prognosis and cisplatin chemosensitivity in bladder cancer.

Methods: Transcriptomic data and clinical information of bladder cancer patients were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Non-negative matrix factorization (NMF) was used to cluster mevalonate metabolism-related genes into distinct metabolic subtypes (C1 and C2). Associations between mevalonate metabolism, clinical characteristics, immune infiltration, and cisplatin resistance were analyzed using Gene Set Variation Analysis (GSVA), Kaplan-Meier survival analysis, single-sample Gene Set Enrichment Analysis (ssGSEA), and in vitro experiments.

Results: NMF clustering classified bladder cancer patients into two metabolic subtypes (C1/C2). The C1, characterized by higher mevalonate metabolism (MVAscore), was associated with a poorer prognosis, shorter overall survival (OS), and higher T-stage and pathological grades. Immune analysis showed lower immune cell infiltration in C1. Immune infiltration analysis revealed significantly lower immune infiltration levels in the C1. Further analysis revealed a positive correlation between mevalonate metabolism and platinum resistance, with a notable increase in mevalonate metabolism observed in cisplatin-resistant bladder cancer cells. In vitro, simvastatin inhibited the proliferation of bladder cancer cells and enhanced their sensitivity to cisplatin.

Discussion: Mevalonate metabolism drives BCa heterogeneity and chemoresistance while suppressing anti-tumor immunity. Its dysregulation serves as both a prognostic biomarker and a target for therapeutic intervention.

Conclusion: Mevalonate metabolism contributes to cisplatin resistance in bladder cancer and represents a potential therapeutic target. Simvastatin targeting this pathway enhances the efficacy of cisplatin, providing a novel personalized chemotherapy strategy.