Multi-Omics Integration Identifies Ferroptosis-Related miRNA–mRNA Networks and Independent Prognostic miRNAs in Triple-Negative Breast Cancer

Abstract

Objective: This study aimed to comprehensively characterize the transcriptomic and proteomic landscape of ferroptosis-associated mRNAs, miRNAs, and proteins, elucidate subtype-specific regulatory networks, and identify potential prognostic biomarkers in triple-negative breast cancer (TNBC). Materials and Methods: Using the TCGA-BRCA cohort for discovery and the METABRIC dataset for validation, we performed differential expression and functional enrichment analyses comparing TNBC and non-TNBC subtypes. An integrated miRNA–mRNA regulatory network was constructed, and multivariable Cox proportional hazards regression analysis was performed to evaluate the prognostic value of the identified biomarkers. Results: TNBC exhibited profound transcriptional dysregulation, characterized by the marked upregulation of the iron-sequestering gene FTMT (log₂FC=5.60) and downregulation of the iron exporter SLC40A1 (log₂FC=-3.13). We identified 197 significantly dysregulated miRNAs, including the overexpressed oncomiR hsa-miR-135b and the suppressed tumor-suppressor miRNA hsa-miR-449a. Functional enrichment analyses consistently highlighted substantial disruptions in iron homeostasis and oxidative stress pathways. Network analysis identified NQO1 and SLC38A1 as central mRNA hubs. Notably, although specific mRNAs, including SLC40A1 and ALOX15, demonstrated prognostic value in univariate analyses, multivariable Cox regression analysis revealed that only hsa-miR-378c and hsa-miR-449a remained significant as independent prognostic factors. Conclusion: This multi-omics integration maps the ferroptosis-related regulatory landscape of TNBC. Although specific mRNAs serve as key structural hubs, hsa-miR-378c and hsa-miR-449a emerge as robust independent prognostic biomarkers, providing important insights into TNBC risk stratification and potential targeted therapeutic strategies.