Breast cancer is a leading cause of cancer mortality among women globally, with over 2.26 million new cases annually, according to GLOBOCAN 2020. This accounts for approximately 25% of all new female cancers and 15.5% of female cancer deaths. To address this critical public health challenge, we conducted a multi-omics study aimed at identifying hub genes, therapeutic targets, and potential natural product-based therapies. We employed weighted gene co-expression network analysis (WGCNA) and differential gene expression analysis to pinpoint hub genes in breast cancer. Regulatory networks for these genes were constructed by re-analyzing chromatin immunoprecipitation sequencing (ChIP-seq) data from breast cancer cell lines. Additionally, single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) were utilized to characterize hub gene expression profiles and their relationships with immune cell clusters and tumor microenvironments. Survival analysis based on mRNA and protein expression levels identified prognostic factors and potential therapeutic targets. Lastly, large-scale virtual screening of natural product compounds revealed leading compounds that target squalene epoxidase (SQLE). Our multi-omics analysis paves the way for more effective clinical treatments for breast cancer.