Short-chain fatty acids (SCFAs) mediated gut breast crosstalk in breast cancer: integrative network analysis of molecular signaling, immune infiltration and prognostic biomarkers

Introduction Breast cancer is a heterogeneous malignancy in which metabolic dysregulation, immune remodelling, and complex host microbiota interactions contribute to disease progression and therapeutic response. Emerging evidence suggests that gut microbiota-derived short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, may act as important molecular mediators linking the gut microbiome to systemic immune and tumor-associated signalling. However, the molecular networks through which SCFA-mediated signalling may influence breast cancer progression and the tumor immune microenvironment remains poorly characterized. This study aimed to investigate the potential regulatory mechanisms underlying the gut-breast axis by integrating SCFA host interaction networks in breast cancer transcriptomic, prognostic, immune infiltration, and drug gene interaction analyses. Methods The SCFA-host interactome was constructed from the combination of HMDB and PubChem data in a protein-protein interaction network. The identification of hub genes was conducted through topological analysis, followed by validation using TCGA-BRCA RNA-seq data, Kaplan-Meier Survival Analysis, TIMER2.0 immune analysis, and DGIdb repurposing analysis. Results The findings indicated that the genes STAT3, HIF1A, and IL6 served as key nodes connecting SCFA signalling and cancer formation. Selected SCFAs, such as propionate, have direct experimental evidence of involvement in the modulation of the JAK2/STAT3 pathway in breast cancer models, while butyrate has been associated with several breast cancer-related signalling and epigenetic mechanisms. Associations were most strongly identified in acetate which was mainly related to metabolic and immune regulatory pathways. This computational analysis did not give a quantitative ranking of the strength of interaction between SCFA and hub genes. In exploratory survival analysis without multiple-testing correction, increased STAT3 and HIF1A expression was associated with unfavourable relapse-free survival. SCFA-associated immune targets showed positive correlations with CD8+ T-cell infiltration. Discussion This study identifies the SCFA-host interactome as an essential regulatory network in breast cancer. Uncovering metabolic and signalling chokepoints such as STAT3 leads to the discovery of new biomarkers for prognosis and drug targets. This highlights the possibility of exploiting the gut-breast axis to increase immune cell penetration.