A Butyrate Metabolism‐Related Gene Signature Predicts Prognosis, Immune Landscape, and Immunotherapy Efficacy in Breast Cancer

Emerging evidence highlights the critical role of metabolic pathways in breast cancer (BC) progression. Here, we developed a butyrate metabolism-specific gene (BMRG) signature to predict clinical outcomes and immunotherapy responses in BC, providing a novel pathway-focused prognostic tool. Using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we identified 102 butyrate metabolism-related differentially expressed genes (DEGs) through the intersection of DEGs, WGCNA-derived key module genes, and BMRGs. Univariate Cox followed by least absolute shrinkage and selection operator (LASSO) analysis identified nine genes to construct a prognostic signature, which served as an independent prognostic factor. Risk stratification revealed distinct immune microenvironment and mutation landscapes between subgroups, with risk scores strongly correlating with immune checkpoint expression. The signature exhibited robust prognostic performance, with AUC values for 3-, 5-, and 7-year overall survival ranging from 0.65-0.69 in TCGA and 0.57-0.77 in independent GEO cohorts. Protein-protein interaction analysis identified ACSL1 as a key hub gene, and functional validation confirmed that ACSL1 knockdown suppressed BC cell proliferation and migration. Our findings establish this novel nine-gene butyrate metabolism-specific signature as a promising prognostic biomarker and potential therapeutic target for BC, providing a metabolism-focused perspective for personalized BC management.