Interplay of Molecular Subtypes Associated with Butyrate Metabolism Elucidates Clinical Characteristics and Tumor Microenvironment in Prostate Cancer.

Emerging evidence underscores the pivotal yet context-dependent role of butyrate metabolism in oncogenic progression; however, the mechanistic landscape of its associated genetic determinants in prostate carcinogenesis remains poorly characterized. This gap presents a critical opportunity to delineate novel metabolic checkpoints that may offer therapeutic vulnerabilities for advanced prostate malignancies. Analyzing prostate cancer (PC) patients from TCGA and GEO databases, we identified 320 BMGs and stratified tumors into two butyrate metabolism-associated clusters. Machine learning and single-cell transcriptome analysis are used for further study. Luciferase reporter assay, qRT-PCR, FISH, and functional assays are applied to investigate the role of FOS. BMC1 correlated with aggressive phenotypes and stromal-rich tumor microenvironments, while BMC2 was linked to cell cycle regulation and DNA repair. A machine learning-derived RSF + GBM prognostic model demonstrated robust predictive accuracy for biochemical recurrence (training C-index: 0.85). BM scores are further associated with tumor mutation burden and differential drug sensitivities. FOS is overexpressed in PC, promotes proliferation and migration via transcriptional suppression of tumor-suppressive miR-27b. Clinical cohorts confirmed FOS's correlation with advanced T stages and recurrence risk. These findings establish BM-based stratification as a prognostic tool and implicate the FOS-miR-27b axis as a therapeutic target, bridging metabolic heterogeneity with molecular mechanisms in PC progression. Our research offers a critical opportunity to delineate novel metabolic checkpoints that may offer therapeutic vulnerabilities for advanced prostate malignancies.