Multi-Omics Integration Identifies the Cholesterol Metabolic Enzyme DHCR24 as a Key Driver in Breast Cancer

Dysregulated cholesterol metabolism is a hallmark of breast cancer (BC), but its key molecular mediators remain unclear. Using an integrated multi-omics approach, including Mendelian randomization, transcriptomic/proteomic database screening, functional assays, and clinical correlation, we identified the cholesterol biosynthesis enzyme DHCR24 as a central metabolic-immune mediator. We found that high DHCR24 mRNA expression is associated with poorer patient prognosis and is elevated in luminal and HER2+ subtypes. Surprisingly, DHCR24 knockdown enhanced malignant phenotypes in MCF7 cells, contrasting its pro-tumor role in patients. Integrated analysis resolved this paradox, revealing that DHCR24 promotes BC progression non-cell-autonomously by remodeling an immunosuppressive tumor microenvironment, rather than by intrinsically driving cancer cell proliferation. Mechanistically, DHCR24 depletion upregulated TP53 and downregulated SQLE. This study establishes DHCR24 as a pivotal metabolic-immune node and a promising therapeutic target for disrupting the cholesterol-immune axis in luminal and HER2+ BC.