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

## TL;DR

This study finds that the cholesterol enzyme DHCR24 helps breast cancer by blocking immune attacks, suggesting new treatment possibilities.

## Contribution

The study identifies DHCR24 as a non-cell-autonomous driver of breast cancer progression through immune suppression.

## Key findings

- High DHCR24 expression is linked to worse breast cancer prognosis and is elevated in luminal and HER2+ subtypes.
- DHCR24 promotes tumor growth by creating an immunosuppressive environment rather than directly driving cancer cell proliferation.

## Abstract

Scientists have long suspected a link between cholesterol and breast cancer, but proving a direct cause was difficult. Our research used genetic analysis to confirm that high cholesterol levels can indeed increase the risk of developing breast cancer. We then identified a key gene, DHCR24, which is involved in cholesterol production and is often found at high levels in breast cancer patients. We discovered that this gene does more than just manage cholesterol; it primarily helps the cancer by creating a protective shield that blocks the body’s immune cells from attacking the tumor. This finding helps explain why drugs that lower cholesterol might be beneficial and points to DHCR24 as a promising new target for treatment. Our work suggests that future therapies focusing on this gene could potentially weaken the tumor’s defenses and make it more vulnerable to the immune system, offering new hope for personalized breast cancer care.

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.