Integrated multi-omics reveals longitudinal metabolic dynamics and reprogramming in bladder cancer

PURPOSE: Bladder cancer (BCa), particularly NMIBC, poses a substantial clinical burden due to its high recurrence rates and the need for lifelong surveillance. While large-scale studies have identified systemic metabolic risk signatures, a critical gap remains in understanding the dynamic, pre-diagnostic evolution of the metabolome and how these systemic alterations relate to early tumor metabolic reprogramming. To address this gap, we used a large prospective cohort with multi-omics data to characterize pre-diagnostic metabolic changes and their links to early tumor metabolic alterations in BCa. EXPERIMENTAL DESIGN: Baseline plasma metabolomics from 48,241 controls and 2,158 BCa cases in the UK Biobank were analyzed to characterize metabolic alterations preceding diagnosis. Targeted metabolomics and transcriptomics were performed in an independent clinical cohort of 107 NMIBC patients and 56 controls. An eight-metabolite plasma classification model was developed and internally validated. Multi-omics integration and functional experiments were conducted to investigate the role of butyrate. RESULTS: 64 circulating metabolites were associated with future BCa risk, predominantly involving lipid and lipoprotein metabolism. Targeted metabolomics identified 24 differential metabolites, including elevated butyric acid and maleic acid in NMIBC. An eight-metabolite plasma panel achieved an area under the receiver operating characteristic curve (AUC) of 0.98 in the held-out test and 0.92 in the validation set, with cross-biofluid validation in urine yielding an AUC of 0.75. Mechanistically, butyrate remodeled chromatin accessibility and activated AP-1 associated transcriptional programs linked to urothelial phenotypic plasticity. CONCLUSIONS: These findings define lipid dysregulation as a hallmark of the pre-diagnostic metabolic landscape of BCa.